JP7397075B2 - Nitration - Google Patents

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JP7397075B2
JP7397075B2 JP2021521965A JP2021521965A JP7397075B2 JP 7397075 B2 JP7397075 B2 JP 7397075B2 JP 2021521965 A JP2021521965 A JP 2021521965A JP 2021521965 A JP2021521965 A JP 2021521965A JP 7397075 B2 JP7397075 B2 JP 7397075B2
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chloroform
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カターエフ ドミトリー
チャン クン
カルボ ロクサン
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Eidgenoessische Technische Hochschule Zurich ETHZ
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Description

本発明は、ニトロ化化合物を調製するための方法に関する。 The present invention relates to a method for preparing nitrated compounds.

ニトロアレーンは、学界と産業界の両方で、医薬品、農薬、染料、溶媒、材料、及び高エネルギー化合物の合成に対する高い需要が続いている。今日でも、ニトロアレーンとニトロヘテロアレーンはほとんど、過剰な硝酸又はＨ2ＳＯ4／ＨＮＯ3などの混合強酸系を使用して最大１３５℃の温度で、それぞれアレーンとヘテロアレーンを求電子ニトロ化することによって合成される。このような酸性反応条件は、酸感受性及び／又は熱感受性官能基に対する耐性の点で限界であり、位置異性体と過剰にニトロ化された副産物の複雑な混合物の形成につながる選択性の問題をもたらす。 Nitroarenes continue to be in high demand in both academia and industry for pharmaceuticals, pesticides, dyes, solvents, materials, and the synthesis of high-energy compounds. Even today, nitroarenes and nitroheteroarenes are mostly produced by electrophilic nitration of arenes and heteroarenes, respectively, using excess nitric acid or mixed strong acid systems such as H 2 SO 4 /HNO 3 at temperatures up to 135°C. It is synthesized by Such acidic reaction conditions are limiting in terms of tolerance to acid-sensitive and/or heat-sensitive functional groups and pose selectivity problems leading to the formation of complex mixtures of regioisomers and overnitrated by-products. bring.

このような方法は危険で環境にやさしくないと言われているが、Ｈ2Ｓ０4／ＨＮＯ3の使用は、ニトロアレーン及びニトロヘテロアレーンを大規模に調製するための基本的な工業的アプローチとして長年にわたって維持されてきた。 Although such methods are said to be dangerous and environmentally unfriendly, the use of H 2 S0 4 /HNO 3 has become a fundamental industrial approach for the large-scale preparation of nitroarenes and nitroheteroarenes. It has been maintained for many years.

ニトロアレーンの最新の位置特異的合成は、ＮＯ2源としての金属硝酸塩（例えばＡｇＮＯ3、Ｂｉ（ＮＯ3）×６Ｈ2Ｏ、Ｆｅ（ＮＯ3）3×９Ｈ2Ｏ、Ｃａ（ＮＯ2）2）やＰｄ、Ｒｈ、又はＣｕ触媒を使用する、ハロゲン化アリール、疑似ハロゲン化物、有機金属化合物、又はカルボン酸塩のイプソニトロ化反応を含む。最も一般的には、これらの方法は酸性反応条件の使用を必要としない。しかし、これらの試薬はしばしば高価であるか調製が困難であり、これらの方法は、特定のクラスのアレーンにのみしか適用できず、小規模に実施されている。 The latest regiospecific synthesis of nitroarenes is based on metal nitrates (e.g. AgNO 3 , Bi(NO 3 ) × 6H 2 O, Fe(NO 3 ) 3 × 9H 2 O, Ca(NO 2 ) 2 as NO 2 sources. ), Pd, Rh, or Cu catalysts. Most commonly, these methods do not require the use of acidic reaction conditions. However, these reagents are often expensive or difficult to prepare, and these methods are only applicable to certain classes of arenes and have been performed on a small scale.

あるいは、ニトロアレーンは、対応する一級アリールアミンの酸化工程を介して調製することができる。しかし、これは追加の化学工程が必要であり、反応条件は、さまざまな官能基には許容されない場合が多い。 Alternatively, nitroarenes can be prepared via an oxidation step of the corresponding primary arylamines. However, this requires additional chemical steps and reaction conditions are often not tolerated by various functional groups.

スケールアップの観点から、上記のすべての方法論は、有毒で高コストの試薬の使用、特定の技術機器の使用、目的の製品を分離するための前処理操作の困難さ、及び化学量論量を超える量の酸性又は金属廃棄物の生成などの現実的な欠点を有し、これらの廃棄はしばしば問題がある。 From a scale-up perspective, all the above methodologies suffer from the use of toxic and high-cost reagents, the use of specific technical equipment, the difficulty of pretreatment operations to isolate the desired products, and the limitations of stoichiometry. Disposal of these is often problematic, with practical drawbacks such as the generation of excessive amounts of acidic or metal waste.

Yan et al, "Recent advances in the synthesis of aromatic nitro compounds", Org. Biomol. Chem., 2013, 11, 2554-2566は、ニトロアレーン及びニトロヘテロアレーンを取得するためのさまざまなアプローチについて詳細に考察している。 Yan et al, "Recent advances in the synthesis of aromatic nitro compounds", Org. Biomol. Chem., 2013, 11, 2554-2566 discuss in detail various approaches to obtain nitroarenes and nitroheteroarenes. are doing.

米国特許第６，４６８，４８７号は、基質をニトロ化するのに有用な触媒を開示している。さらに米国特許第５，９４６，６３８号は、オルト及びパラ指向置換基を活性化する少なくとも１つの環を有する置換芳香族化合物のニトロ化方法を開示している。この方法は前記芳香族化合物を、固体の酸性小孔径ゼオライト触媒の存在下で７０～９０℃の範囲の温度で加熱する工程と、加熱された混合物に９０～９８％の濃度を有する濃硝酸を添加する工程とを含み、こうしてパラ及びオルトニトロ異性体の比率が高い生成物が得られる。 US Pat. No. 6,468,487 discloses catalysts useful for nitrating substrates. Further, US Pat. No. 5,946,638 discloses a method for nitration of substituted aromatic compounds having at least one ring that activates ortho- and para-directed substituents. This method involves heating the aromatic compound at a temperature in the range of 70-90°C in the presence of a solid acidic small-pore zeolite catalyst and adding concentrated nitric acid having a concentration of 90-98% to the heated mixture. adding, thus obtaining a product with a high proportion of para- and ortho-nitro isomers.

従って、上記のアプローチの適用は、特に複雑分子の後期段階の官能基化を介する創薬について制限されている。 Therefore, the application of the above approach is limited, especially for drug discovery through late-stage functionalization of complex molecules.

従って本発明の問題は、少なくとも１つの芳香環又はヘテロ芳香環を含む化合物のニトロ化のための、より一般的で、安価で、実用的で、安全で、環境に優しい方法を提供することである。 It is therefore an object of the present invention to provide a more general, cheap, practical, safe and environmentally friendly method for the nitration of compounds containing at least one aromatic or heteroaromatic ring. be.

この問題は、請求項１に記載の方法によって解決される。さらに好ましいのは、従属請求項の対象である。 This problem is solved by the method according to claim 1. Further preference is given to the subject matter of the dependent claims.

驚くべきことに、本発明の方法は、少なくとも１つの置換又は非置換芳香環又はヘテロ芳香環を含むアレーン化合物を、優れた化学効率でニトロ化することを可能にすることが見出された。本発明のニトロ化剤は優れた反応性を有し、芳香環又はヘテロ芳香環を含む様々な化合物を、穏やかな反応条件下で６０～１００％、好ましくは８０～１００％の収率でニトロ化するために使用することができる。特に本発明の方法は、異なるサイズ及び複雑さの有機分子へのＮＯ2基の迅速かつ非常に効率的な組み込みを可能にする。さらに本発明の方法は、出発物質の環境に優しく安全なモノニトロ化を実行することを可能にし、過剰ニトロ化、及びしばしば所望の生成物から分離することが困難である望ましくない酸化副産物の生成を回避する。さらに本発明の方法は、副産物としてサッカリン又はサッカリン誘導体を生成し、これを回収して、ニトロ化試薬の合成にさらに再利用することができる。 Surprisingly, it has been found that the process of the invention allows arene compounds containing at least one substituted or unsubstituted aromatic or heteroaromatic ring to be nitrated with excellent chemical efficiency. The nitrating agent of the present invention has excellent reactivity and can nitrate various compounds containing aromatic or heteroaromatic rings with a yield of 60-100%, preferably 80-100% under mild reaction conditions. It can be used to make In particular, the method of the invention allows rapid and highly efficient incorporation of NO2 groups into organic molecules of different size and complexity. Furthermore, the process of the invention makes it possible to carry out an environmentally friendly and safe mononitration of starting materials, avoiding overnitration and the formation of undesired oxidation by-products that are often difficult to separate from the desired product. To avoid. Furthermore, the method of the present invention produces saccharin or saccharin derivatives as a by-product, which can be recovered and further reused in the synthesis of nitration reagents.

化合物（Ａ）は、本発明の方法の出発物質であり、少なくとも１つの置換又は非置換芳香環又はヘテロ芳香環を含み、前記ヘテロ芳香環は、酸素、硫黄、リン、セレン、及び窒素から成る群から選択される少なくとも１つのヘテロ原子を含む。本発明の方法は、化合物（Ａ）が式（Ｉ）の化合物と反応する反応工程を含む。

Figure 0007397075000001
（式中、Ｙは水素及びニトロから成る群から選択される）。 Compound (A) is a starting material for the process of the invention and comprises at least one substituted or unsubstituted aromatic or heteroaromatic ring, said heteroaromatic ring consisting of oxygen, sulfur, phosphorus, selenium and nitrogen. at least one heteroatom selected from the group. The method of the invention includes a reaction step in which compound (A) is reacted with a compound of formula (I).
Figure 0007397075000001
 (wherein Y is selected from the group consisting of hydrogen and nitro).

本発明の方法の化合物（Ａ）は、少なくとも１つの置換又は非置換芳香環又はヘテロ芳香環を含み、前記ヘテロ芳香環は、酸素、硫黄、リン、セレン、及び窒素から成る群から選択される少なくとも１つのヘテロ原子を含む。化合物（Ａ）は、より大きな複雑分子の構造部分として、少なくとも１つの置換又は非置換環を含むか、又は前記少なくとも１つの非置換又は置換芳香環のみからなる。すなわち「化合物（Ａ）」という表現は、アレーンとヘテロアレーン、並びにこれらの化学構造中に１つ以上の芳香環又はヘテロ芳香環を含む化合物、例えばエストロン、エストラジオール、及びエストリオールを包含する。２つ以上の芳香環又はヘテロ芳香環が存在する場合、これらの環は、互いに一緒に融合されるか、又はアルキレン基などの結合を介して互いに接続されることができる。言い換えれば、化合物（Ａ）は、置換又は非置換の芳香環又はヘテロ芳香環を含むか又はそれからなる小、中、又は大有機化合物であり得る。化合物（Ａ）は、ステロイド誘導体、イブプロフェン誘導体、及びデラマニド誘導体などの多様な官能基を任意選択的に有する複雑分子でさえあり得る。 Compound (A) of the process of the invention comprises at least one substituted or unsubstituted aromatic or heteroaromatic ring, said heteroaromatic ring being selected from the group consisting of oxygen, sulfur, phosphorus, selenium, and nitrogen. Contains at least one heteroatom. Compound (A) contains at least one substituted or unsubstituted ring as a structural part of a larger complex molecule, or consists solely of said at least one unsubstituted or substituted aromatic ring. Thus, the expression "compound (A)" includes arenes and heteroarenes, as well as compounds containing one or more aromatic or heteroaromatic rings in their chemical structure, such as estrone, estradiol, and estriol. If two or more aromatic or heteroaromatic rings are present, these rings can be fused together or connected to each other via bonds such as alkylene groups. In other words, compound (A) can be a small, medium, or large organic compound containing or consisting of substituted or unsubstituted aromatic or heteroaromatic rings. Compound (A) can even be a complex molecule, optionally having diverse functional groups, such as steroid derivatives, ibuprofen derivatives, and delamanid derivatives.

ニトロ化反応の位置選択性を、当業者は予測することができる（例えば、A. Klumpp; Arene Chemistry: Reaction Mechanisms and Methods for Aromatic Compounds, 2016, (John Wiley and Sons, Inc)、及び C. J. Nalbandian, Z. E. Brown, E. Alvarez, J. L. Gustafson Org. Lett. 2018, 20, 11, 3211-3214; C. Xu, B. Ma, Q. Shen Angew. Chem. Int. Ed. 2014, 53, 9316-9320; P. Zhang, M. Li, X.-S. Xue, C. Xu, Q. Zhao, Y. Liu, H. Wang, Y. Guo, L. Lu, Q. Shen J. Org. Chem. 2016, 81, 7486-7509を参照）。 The regioselectivity of nitration reactions can be predicted by those skilled in the art (e.g., A. Klumpp; Arene Chemistry: Reaction Mechanisms and Methods for Aromatic Compounds, 2016, (John Wiley and Sons, Inc), and C. J. Nalbandian, Z. E. Brown, E. Alvarez, J. L. Gustafson Org. Lett. 2018, 20, 11, 3211-3214; C. Xu, B. Ma, Q. Shen Angew. Chem. Int. Ed. 2014, 53, 9316-9320; P. Zhang, M. Li, X.-S. Xue, C. Xu, Q. Zhao, Y. Liu, H. Wang, Y. Guo, L. Lu, Q. Shen J. Org. Chem. 2016, 81, 7486-7509).

「ヘテロ芳香環」という用語は、芳香環の１つ以上の炭素原子が、窒素、酸素、硫黄、セレン、及びリンから成る群から選択されるヘテロ原子で置換されている芳香環について使用される。 The term "heteroaromatic ring" is used for an aromatic ring in which one or more carbon atoms of the aromatic ring are replaced with a heteroatom selected from the group consisting of nitrogen, oxygen, sulfur, selenium, and phosphorus. .

化合物（Ａ）の前記少なくとも１つの芳香環又はヘテロ芳香環は、非置換であるか、又は１つ以上の有機残基Ｒで置換されていてもよい。 Said at least one aromatic ring or heteroaromatic ring of compound (A) may be unsubstituted or substituted with one or more organic residues R.

好ましくは、前記有機残基Ｒは、フルオロ、クロロ、ブロモ、ヨード、アミノ、シアノ、ヒドロキシ、ニトロ、Ｃ1-12アルキル、Ｃ2-15アルケニル、Ｃ2-15アルキニル、Ｃ3-15シクロアルキル、Ｃ3-15シクロアルケニル、シクロアルキニル、Ｃ3-5アルキレン、Ｃ3-5シクロアルキレン、Ｃ3-5アルケニレン、Ｃ3-5アルキニレン、ハロ－Ｃ1-6アルキル、ヒドロキシ－Ｃ1-6アルキル、ハロ－Ｃ3-15シクロアルキル、Ｃ1-10アルコキシ、Ｃ3-5シクロアルコキシ、アルキレンジオキシ、Ｃ1-6アシル、Ｃ3-6シクロアシル、Ｃ1-6アシルオキシ、Ｃ3-6シクロアシルオキシ、アリールアルキル、ヘテロアリールアルキル、アリール、及びヘテロアリール基から成る群から選択され、及び／又はシクロアルキル、アリール、及びヘテロアリール環から選択される他の環とアニーリングされた環系を形成し得る。 Preferably, the organic residue R is fluoro, chloro, bromo, iodo, amino, cyano, hydroxy, nitro, C 1-12 alkyl, C 2-15 alkenyl, C 2-15 alkynyl, C 3-15 cycloalkyl. , C 3-15 cycloalkenyl, cycloalkynyl, C 3-5 alkylene, C 3-5 cycloalkylene, C 3-5 alkenylene, C 3-5 alkynylene, halo- C 1-6 alkyl , hydroxy-C 1-6 Alkyl, halo-C 3-15 cycloalkyl, C 1-10 alkoxy, C 3-5 cycloalkoxy, alkylenedioxy, C 1-6 acyl, C 3-6 cycloacyl, C 1-6 acyloxy, C 3-6 forming a ring system selected from the group consisting of cycloacyloxy, arylalkyl, heteroarylalkyl, aryl, and heteroaryl groups and/or annealed with other rings selected from cycloalkyl, aryl, and heteroaryl rings; It is possible.

「アルキル」は、単独で使用されるか、又は「ハロアルキル」若しくは「アリールアルキル」などの別の基の一部として使用されるかにかかわらず、単一の基を有する直鎖又は分岐鎖の脂肪族炭化水素基を意味する。アルキル基の例としては、メチル、プロピル、イソプロピル、ブチル、ｎ－ブチル、イソブチル、ｓｅｃ－ブチル、ｔｅｒｔ－ブチル、ペンチル、ヘキシル、ヘプチル、セチルなどが挙げられる。「低級アルキル」という用語は、１～約１２個の炭素原子を有し、単一の基を有する直鎖又は分岐炭化水素基を意味する。分岐アルキルとは、メチル、エチル、又はプロピルなどの１つ以上の低級アルキル基が直鎖アルキル鎖に結合していることを意味する。 "Alkyl" means a straight or branched chain having a single group, whether used alone or as part of another group such as "haloalkyl" or "arylalkyl". means an aliphatic hydrocarbon group. Examples of alkyl groups include methyl, propyl, isopropyl, butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, cetyl, and the like. The term "lower alkyl" means a straight chain or branched hydrocarbon group having a single radical having 1 to about 12 carbon atoms. Branched alkyl means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a straight alkyl chain.

「ハロアルキル」という用語は、アルキル炭素原子のいずれか１つ以上が、フルオロ、クロロ、ブロモ、及びヨードから成る群から選択されるハロゲンで置換されている残基を包含する。ハロアルキル基の例には、例えばフルオロメチル、ジフルオロメチル、トリフルオロメチル、クロロメチル、ジクロロメチル、及びトリクロロメチルが含まれる。 The term "haloalkyl" includes residues in which any one or more of the alkyl carbon atoms is substituted with a halogen selected from the group consisting of fluoro, chloro, bromo, and iodo. Examples of haloalkyl groups include, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, and trichloromethyl.

「ヒドロキシアルキル」という用語は、アルキル炭素原子のいずれか１つ以上がヒドロキシで置換されている残基を包含する。ヒドロキシアルキル残基の例には、ヒドロキシメチル、ヒドロキシエチル、ヒドロキシブチル、ヒドロキシプロピルが含まれる。 The term "hydroxyalkyl" includes residues in which any one or more alkyl carbon atoms are replaced with hydroxy. Examples of hydroxyalkyl residues include hydroxymethyl, hydroxyethyl, hydroxybutyl, hydroxypropyl.

「シクロアルキル」という用語は、単一の基を有する３～１５個の炭素原子の非芳香族単環式又は多環式環系を意味する。好ましい単環式シクロアルキル環には、シクロペンチル、シクロヘキシル、及びシクロヘプチルが含まれる。例示的な多環式シクロアルキル環には、１－デカリン、アダマント－（１－又は２－）イル、及びノルボルニルが含まれる。 The term "cycloalkyl" means a non-aromatic monocyclic or polycyclic ring system of 3 to 15 carbon atoms having a single radical. Preferred monocyclic cycloalkyl rings include cyclopentyl, cyclohexyl, and cycloheptyl. Exemplary polycyclic cycloalkyl rings include 1-decalin, adamant-(1- or 2-)yl, and norbornyl.

本明細書で使用される「アルケニル」という用語は、単一の基を有し、炭素－炭素二重結合を含み、鎖中に約２～約１５個の炭素原子を有する直鎖又は分枝鎖であり得る脂肪族炭化水素基を意味する。「分岐した」アルケニルとは、メチル、エチル、又はプロピルなどの１つ以上の低級アルキル基が直鎖状のアルケニル鎖に結合していることを意味する。例示的なアルケニル基には、エテニル、プロペニル、ｎ－ブテニル、ｉ－ブテニル、３－メチルブタ－２－エニル、ｎ－ペンテニル、ヘプテニル、オクテニル、及びデセニルが含まれる。 As used herein, the term "alkenyl" refers to a straight or branched chain having a single radical, containing a carbon-carbon double bond, and having about 2 to about 15 carbon atoms in the chain. means an aliphatic hydrocarbon group which may be a chain. "Branched" alkenyl means that one or more lower alkyl groups, such as methyl, ethyl, or propyl, are attached to a straight alkenyl chain. Exemplary alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, and decenyl.

「シクロアルケニル」という用語は、単一の基を有し、炭素－炭素二重結合を含み、３～１５個の炭素原子を有する非芳香族単環式又は多環式環系を意味する。例示的な単環式シクロアルケニル環には、シクロペンテニル、シクロヘキセニル、又はシクロヘプテニルが含まれる。例示的な多環式シクロアルケニル環はノルボルネニルである。 The term "cycloalkenyl" means a non-aromatic monocyclic or polycyclic ring system having a single radical, containing a carbon-carbon double bond, and having from 3 to 15 carbon atoms. Exemplary monocyclic cycloalkenyl rings include cyclopentenyl, cyclohexenyl, or cycloheptenyl. An exemplary polycyclic cycloalkenyl ring is norbornenyl.

「アルキニル」という用語は、単一の基を有し、炭素－炭素三重結合を含み、鎖中に約２～約１５個の炭素原子を有する直鎖又は分枝鎖であり得る脂肪族炭化水素基を意味する。「分岐」アルキニルとは、メチル、エチル、又はプロピルなどの１つ以上の低級アルキル基が直鎖アルキニル鎖に結合していることを意味する。「低級アルキニル」は、直鎖又は分枝鎖であり得る鎖中に約２～約４個の炭素原子を有するアルキニル基を意味する。 The term "alkynyl" refers to an aliphatic hydrocarbon having a single radical, containing a carbon-carbon triple bond, and which may be straight or branched chain having from about 2 to about 15 carbon atoms in the chain. means base. "Branched" alkynyl means that one or more lower alkyl groups, such as methyl, ethyl, or propyl, are attached to a straight alkynyl chain. "Lower alkynyl" means an alkynyl group having about 2 to about 4 carbon atoms in the chain which may be straight or branched.

「シクロアルキニル」という用語は、単一の基を有し、炭素－炭素三重結合を含み、３～１０個の炭素原子を有する非芳香族単環式又は多環式環系を意味する。例示的な単環式シクロアルキニル環はシクロオクチニルである。 The term "cycloalkynyl" means a non-aromatic monocyclic or polycyclic ring system having a single radical, containing a carbon-carbon triple bond, and having from 3 to 10 carbon atoms. An exemplary monocyclic cycloalkynyl ring is cyclooctynyl.

「アルキレン」という用語は、２つの基を有する直鎖又は分岐鎖の脂肪族炭化水素基を意味する。例示的なアルキレン基は、メチレン及びエチレンである。 The term "alkylene" means a straight or branched aliphatic hydrocarbon group having two groups. Exemplary alkylene groups are methylene and ethylene.

「アルケニレン」という用語は、少なくとも１つの炭素－炭素二重結合及び２つの基を有する直鎖又は分岐鎖の脂肪族炭化水素基を意味する。 The term "alkenylene" means a straight or branched aliphatic hydrocarbon group having at least one carbon-carbon double bond and two groups.

「アルキニレン」という用語は、単一の炭素－炭素三重結合及び２つの基を有する直鎖又は分岐鎖の脂肪族炭化水素基を意味する。 The term "alkynylene" means a straight or branched chain aliphatic hydrocarbon group having a single carbon-carbon triple bond and two groups.

「アリール」という用語は、ニトロ化される芳香環又はヘテロ芳香環に結合し、６個又は１０個の共鳴電子を含む芳香族炭素環式基を意味する。例示的なアリール基には、フェニル及びナフチルが含まれる。 The term "aryl" means an aromatic carbocyclic group attached to an aromatic or heteroaromatic ring that is nitrated and containing 6 or 10 resonant electrons. Exemplary aryl groups include phenyl and naphthyl.

「アリーレン」という用語は、そのうちの１つがニトロ化される芳香環又はヘテロ芳香環に結合して２つの基を有し、６個又は１０個の共鳴電子とを含む芳香族炭素環式基を意味する。例示的なアリーレン基には、フェニレン及びナフチレンが含まれる。 The term "arylene" refers to an aromatic carbocyclic group having two groups attached to an aromatic or heteroaromatic ring, one of which is nitrated, and containing 6 or 10 resonant electrons. means. Exemplary arylene groups include phenylene and naphthylene.

「アリールアルキル」という用語は、直鎖又は分岐鎖の脂肪族炭化水素基で置換されている、上記で定義されたアリール基を意味する。 The term "arylalkyl" means an aryl group as defined above substituted with a straight or branched aliphatic hydrocarbon group.

「ヘテロアリールアルキル」という用語は、環中に少なくとも１つの炭素原子を含み、６個又は１０個の共鳴電子を含む、５～１０員の芳香族単環式又は多環式環系を含む上記で定義されたヘテロアリール基を意味し、ここで、環原子の１つ以上は炭素以外の元素、例えば、窒素、酸素、硫黄、セレン、又はリンであり、及びここで、前記ヘテロアリール基は、直鎖又は分岐鎖の脂肪族炭化水素基を含む上記で定義されたアルキル基で置換される。 The term "heteroarylalkyl" refers to a 5- to 10-membered aromatic monocyclic or polycyclic ring system containing at least one carbon atom in the ring and containing 6 or 10 resonating electrons. means a heteroaryl group as defined in , substituted with an alkyl group as defined above, including a straight-chain or branched aliphatic hydrocarbon group.

「複素環式」という用語は、１つがニトロ化される芳香環又はヘテロ芳香環に結合してしている単一の基を有し、環内に炭素以外の１つ以上の原子を含む、環状化合物を意味する。環は、飽和、部分飽和、及び不飽和のヘテロ原子含有基であり得て、ここでヘテロ原子は、窒素、硫黄、及び酸素から選択され得る。飽和複素環式基の例には、ピロリジニル、イミダゾリジニル、ピペリジノ、ピペラジニルなどなどの１～４個の窒素原子を含む飽和３～６員複素単環式基；チアゾリジニルなどの１～２個の酸素原子と１～３個の窒素原子を含む飽和３～６員のヘテロ単環式基が含まれる。部分的に飽和した複素環式基の例には、ジヒドロチオフェン、ジヒドロピラン、ジヒドロフランが含まれる。 The term "heterocyclic" has a single group attached to an aromatic or heteroaromatic ring, one of which is nitrated, and contains one or more atoms other than carbon in the ring. means a cyclic compound. The rings can be saturated, partially saturated, and unsaturated heteroatom-containing groups, where the heteroatoms can be selected from nitrogen, sulfur, and oxygen. Examples of saturated heterocyclic groups include saturated 3- to 6-membered heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidino, piperazinyl, etc.; 1 to 2 oxygen atoms, such as thiazolidinyl. and saturated 3- to 6-membered heteromonocyclic groups containing 1 to 3 nitrogen atoms. Examples of partially saturated heterocyclic groups include dihydrothiophene, dihydropyran, dihydrofuran.

「アシル」という用語は、Ｈ－ＣＯ又はアルキル－ＣＯ－基を意味し、アルキル基は上記で定義された通りである。例示的なアシル基には、ホルミル、アセチル、プロパノイル、２－メチルプロパノイル、ブタノイル、及びパルミトイルが含まれる。「シクロアシル」は、Ｈ－ＣＯ－又はシクロアルキル－ＣＯ－基を意味し、シクロアルキル基は上記で定義された通りである。 The term "acyl" means an H--CO or alkyl-CO- group, where the alkyl group is as defined above. Exemplary acyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl, butanoyl, and palmitoyl. "Cycloacyl" means a H--CO- or cycloalkyl-CO- group, where the cycloalkyl group is as defined above.

「アシルオキシ」という用語は、アシル－Ｏ－基を意味し、アシル基は上記で定義された通りである。「シクロアシルオキシ」という用語は、シクロアシル－Ｏ－基を意味を意味し、シクロアシル基は上記で定義された通りである。 The term "acyloxy" means an acyl-O- group, where the acyl group is as defined above. The term "cycloacyloxy" means a cycloacyl-O- group, where the cycloacyl group is as defined above.

「アルコキシ」という用語は、アルキル－Ｏ－基を意味し、アルキル基は上記で定義された通りである。例示的なアルコキシ基には、メトキシ、エトキシ、ｎ－プロポキシ、ｉ－プロポキシ、ｎ－ブトキシ、及びヘプトキシが含まれる。「シクロアルコキシ」という用語は、シクロアルキル－Ｏ－基を意味を意味し、シクロアルキル基は上記で定義された通りである。例示的なシクロアルコキシ基には、シクロペンチルオキシが含まれる。 The term "alkoxy" means an alkyl-O- group, where the alkyl group is as defined above. Exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and heptoxy. The term "cycloalkoxy" means a cycloalkyl-O- group, where the cycloalkyl group is as defined above. Exemplary cycloalkoxy groups include cyclopentyloxy.

「アルキレンジオキシ」という用語は、Ｒ'－Ｏ－アルキレン－Ｏ－Ｒ''基を意味し、アルキレンは上記で定義された通りであり、Ｒ'及びＲ''は、アルキル、アルケニル、アルキニル、シクロアルキル、シクロアルケニル、シクロアルキニル、アリール、ヘテロアリール、複素環から成る群から選択され、又はＲ'及びＲ''は一緒になって、単一のアルキレン、アルケニリエン、アルキニレン、シクロアルキレン、シクロアルケニレン、シクロアルキニレン、又はアリーレン基である。 The term "alkylenedioxy" means the group R'-O-alkylene-O-R'', where alkylene is as defined above, and R' and R'' are alkyl, alkenyl, alkynyl , cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocycle, or R' and R'' taken together represent a single alkylene, alkenyliene, alkynylene, cycloalkylene, cyclo It is alkenylene, cycloalkynylene, or arylene group.

「アミド」又は「アミノカルボニル」という用語は、以下に示す－Ｃ（Ｏ）ＮＨ2を意味する：

Figure 0007397075000002
The term "amide" or "aminocarbonyl" means -C(O) NH2 as shown below:
Figure 0007397075000002

「アミノ」という用語は、基－ＮＨ2を意味する。 The term "amino" refers to the group -NH 2 .

「カルバミド」又は「（アミノカルボニル）アミノ」という用語は、以下に示す式Ｈ2ＮＣＯＮＨ－を有する基である：

Figure 0007397075000003
The term "carbamide" or "(aminocarbonyl)amino" is a group having the formula H 2 NCONH- as shown below:
Figure 0007397075000003

「カルバミル」という用語は、以下に示すＮＨ2ＣＯ－基である：

Figure 0007397075000004
The term "carbamyl" is an NH 2 CO- group as shown below:
Figure 0007397075000004

「カルボキシ」又は「カルボキシル」という用語は、単独で使用される場合でも、又は他の基、例えば「カルボキシアルキル」と組み合わせて使用される場合でも、以下に示す－ＣＯ2Ｈを意味する：

Figure 0007397075000005
The term "carboxy" or "carboxyl", whether used alone or in combination with other groups such as "carboxyalkyl", refers to -CO 2 H:
Figure 0007397075000005

「カルボキサミド」という用語は、以下に示す－ＮＨＣ（Ｏ）－を意味する：

Figure 0007397075000006
The term "carboxamide" means -NHC(O)- as shown below:
Figure 0007397075000006

「カルボニル」という用語は、単独で使用される場合でも、「アルコキシカルボニル」などの他の用語と組み合わせて使用される場合でも、－（Ｃ＝Ｏ）－を意味する。「アルコキシカルボニル」という用語は、酸素原子を介してカルボニル基に結合した、上記で定義されたアルコキシ基を含む基を意味する。 The term "carbonyl", whether used alone or in combination with other terms such as "alkoxycarbonyl", means -(C=O)-. The term "alkoxycarbonyl" means a group comprising an alkoxy group as defined above attached through an oxygen atom to a carbonyl group.

「誘導体」という用語は、母化合物（Ａ）の構造及び特性が著しく変化しない程度に変化している化合物を意味する。 The term "derivative" means a compound in which the structure and properties of the parent compound (A) are changed without significantly changing them.

本発明の１つの実施態様において、化合物（Ａ）の少なくとも１つの芳香環又はヘテロ芳香環は、水素ではない少なくとも１つの残基Ｒを含む。Ｒは、好ましくは上記で定義された基から選択される。 In one embodiment of the invention, at least one aromatic or heteroaromatic ring of compound (A) contains at least one residue R that is not hydrogen. R is preferably selected from the groups defined above.

好ましくは、化合物（Ａ）及び最も好ましくは化合物（Ａ）の芳香環又はヘテロ芳香環は、少なくとも１つの酸感受性残基を含む。すなわち、化合物（Ａ）の分子構造のどこかに、及び／又はニトロ化される芳香環又はヘテロ芳香環上に、少なくとも１つの酸感受性基が直接存在してもよい。酸感受性残基という用語は、本発明の文脈において、酸の存在下で、特にＨ2Ｓ０4及び／又はＨＮＯ3の存在下で、負の影響を受ける残基を意味する。最も好ましくは、前記酸感受性残基は、ジフルオロメトキシ、トリフルオロメトキシ、ジフルオロメチルチオ、トリフルオロメチルチオ、クロロ、ヨード、メトキシ、エトキシ、プロポキシ、ブトキシ、アミノ、メチルアミノ、ジメチルアミノ、ホルミル、メトキシカルボニル、エトキシカルボニル、ｔｅｒｔ－ブトキシカルボニル、塩化アシル、酸無水物、カルボン酸エステル、スルホン酸エステル、アルキルエステル、カルボキシ、ケタール、アセタール、ヒドラゾン、及び４，４，５，５－テトラメチル－１，３，２－ジオキサボロラニルから成る群から選択される。 Preferably, compound (A) and most preferably the aromatic or heteroaromatic ring of compound (A) contains at least one acid-sensitive residue. That is, at least one acid-sensitive group may be present somewhere in the molecular structure of compound (A) and/or directly on the aromatic or heteroaromatic ring to be nitrated. The term acid-sensitive residue, in the context of the present invention, means a residue that is negatively affected in the presence of acids, in particular in the presence of H 2 SO 4 and/or HNO 3 . Most preferably, said acid-sensitive residues are difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio, chloro, iodo, methoxy, ethoxy, propoxy, butoxy, amino, methylamino, dimethylamino, formyl, methoxycarbonyl, Ethoxycarbonyl, tert-butoxycarbonyl, acyl chloride, acid anhydride, carboxylic acid ester, sulfonic acid ester, alkyl ester, carboxy, ketal, acetal, hydrazone, and 4,4,5,5-tetramethyl-1,3, selected from the group consisting of 2-dioxaborolanyl;

好ましくは、化合物（Ａ）の芳香環又はヘテロ芳香環は、少なくとも１つの電子供与基（ＥＤＧ）を残基として含む。芳香環又はヘテロ芳香環上の前記電子供与基の位置は、当業者が環上のニトロ化の位置を予測することを可能にする（Douglas A. Klumpp; Arene Chemistry: Reaction Mechanisms and Methods for Aromatic Compounds, 2016, John Wiley and Sons, Inc.）。前記電子供与基は、好ましくはアミノ、カルバモイル、アルキルアミノカルボニル、カルボキサミド、メルカプト、アルキルチオ、ヒドロキシ、アルコキシ、アルキル、アシルオキシ、アリール、ヘテロアリール、アルケニル、及びアルキニルから成る群から選択される。最も好ましくはＥＤＧは、アミノ、メチル、エチル、フェニル、メトキシ、及びエトキシから成る群から選択される。１つの好適な実施態様において、芳香環又はヘテロ芳香環は、同じかまたは異なっていてもよい１つ、２つ、又は３つのＥＤＧを含む。 Preferably, the aromatic ring or heteroaromatic ring of compound (A) contains at least one electron donating group (EDG) as a residue. The position of said electron-donating group on the aromatic or heteroaromatic ring allows the person skilled in the art to predict the position of nitration on the ring (Douglas A. Klumpp; Arene Chemistry: Reaction Mechanisms and Methods for Aromatic Compounds , 2016, John Wiley and Sons, Inc.). Said electron-donating group is preferably selected from the group consisting of amino, carbamoyl, alkylaminocarbonyl, carboxamide, mercapto, alkylthio, hydroxy, alkoxy, alkyl, acyloxy, aryl, heteroaryl, alkenyl, and alkynyl. Most preferably EDG is selected from the group consisting of amino, methyl, ethyl, phenyl, methoxy, and ethoxy. In one preferred embodiment, the aromatic or heteroaromatic ring contains 1, 2, or 3 EDGs, which may be the same or different.

好ましくは、化合物（Ａ）の芳香環又はヘテロ芳香環は、少なくとも１つの電子求引基（ＥＷＧ）を残基として含む。芳香環又はヘテロ芳香環上の前記電子供与基の位置は、当業者が環上のニトロ化の位置を予測することを可能にする（Douglas A. Klumpp; Arene Chemistry: Reaction Mechanisms and Methods for Aromatic Compounds, 2016, John Wiley and Sons, Inc.）。前記電子吸引基は、好ましくは、フルオロ、クロロ、ブロモ、ヨード、アシル、カルボキシ、ベンゾイル、カルボニル、アルデヒド、アリールスルホニル、ハロアルキル、シアノ、及び２，５－ジオキソピロリジニル群から成る群から選択される電子吸引基から成る群から、好ましくは選択される。最も好ましくはＥＷＤは、フルオロ、クロロ、ブロモ、ヨード、メトキシカルボニル、エトキシカルボニル、ｔｅｒｔ－ブトキシカルボニル、トリフルオロメチル、及びジフルオロメチルから成る群から選択される。１つの好適な実施態様において、芳香環又はヘテロ芳香環は、同じかまたは異なっていてもよい１つ、２つ、又は３つのＥＷＤを含む。 Preferably, the aromatic ring or heteroaromatic ring of compound (A) contains at least one electron-withdrawing group (EWG) as a residue. The position of said electron-donating group on the aromatic or heteroaromatic ring allows the person skilled in the art to predict the position of nitration on the ring (Douglas A. Klumpp; Arene Chemistry: Reaction Mechanisms and Methods for Aromatic Compounds , 2016, John Wiley and Sons, Inc.). Said electron withdrawing group is preferably selected from the group consisting of fluoro, chloro, bromo, iodo, acyl, carboxy, benzoyl, carbonyl, aldehyde, arylsulfonyl, haloalkyl, cyano, and 2,5-dioxopyrrolidinyl group. is preferably selected from the group consisting of electron-withdrawing groups. Most preferably the EWD is selected from the group consisting of fluoro, chloro, bromo, iodo, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, trifluoromethyl, and difluoromethyl. In one preferred embodiment, the aromatic or heteroaromatic ring contains 1, 2, or 3 EWDs, which may be the same or different.

別の好適な実施態様において、化合物（Ａ）の芳香環又はヘテロ芳香環は、１つ又は２つのＥＤＧ及び１つ又は２つのＥＷＤを含む。 In another preferred embodiment, the aromatic or heteroaromatic ring of compound (A) comprises one or two EDGs and one or two EWDs.

好ましくは、化合物（Ａ）は、５員又は６員の置換又は非置換の芳香環又はヘテロ芳香環を含むか、又はそれからなる。すなわち本発明の１つの実施態様において、前記５員又は６員の置換又は非置換の芳香環又はヘテロ芳香環は、より大きな分子の足場の一部である。本発明の別の実施態様において、前記５員又は６員の置換又は非置換の芳香環又はヘテロ芳香環は、化合物（Ａ）である。好ましくは５員又は６員の置換芳香環又はヘテロ芳香環は、好ましくは１つ以上の酸感受性の電子供与基及び／又は電子吸引基によって置換される。 Preferably, compound (A) comprises or consists of a 5- or 6-membered substituted or unsubstituted aromatic or heteroaromatic ring. Thus, in one embodiment of the invention, said 5- or 6-membered substituted or unsubstituted aromatic or heteroaromatic ring is part of a larger molecular scaffold. In another embodiment of the present invention, the 5- or 6-membered substituted or unsubstituted aromatic ring or heteroaromatic ring is compound (A). The preferably 5- or 6-membered substituted aromatic or heteroaromatic ring is preferably substituted by one or more acid-sensitive electron-donating and/or electron-withdrawing groups.

本発明の別の実施態様において、化合物（Ａ）は、置換されていてもされなくてもよい２～５個の芳香環又はヘテロ芳香環を含む縮合芳香環又はヘテロ芳香環系を含むか、又はそれからなる。置換された縮合芳香環又はヘテロ芳香環は、好ましくは、１つ以上の酸感受性の電子供与基及び／又は電子吸引基によって置換される。 In another embodiment of the invention, compound (A) comprises a fused aromatic ring or heteroaromatic ring system comprising 2 to 5 aromatic or heteroaromatic rings, which may or may not be substituted; or consists of it. The substituted fused aromatic or heteroaromatic ring is preferably substituted by one or more acid-sensitive electron donating and/or electron withdrawing groups.

好ましくはヘテロ芳香環又は環系は、ピロール、チオフェン、フラン、イミダゾール、チアゾール、ピリミジン、ピリジン、ピラジン、ピリダジン、イソキサゾール、オキサゾール、インドール、イソインドール、インドリジン、キノリン、イソキノリン、プリン、カルバゾール、ジベンゾフラン、アクリジン、プリン、グアニン、キサンチン、尿酸、ベンゾチオフェン、ベンゾフラン、ジベンゾチオフェン、チアンスレン、キサンテン、フェノキサチイン、イソキノリン、フタラジン、１，８－ナフチドリン、キナゾリン、キノキサリン、シンノリン、プテリジン、ペリミジン、１，７－フェナントロリン、フェナジン、ホスフィンドール、フタルイミド、フラザン、及びホスフィノリン、最も好ましくはピリジン、ピリミジン、フラン、及びフタルイミドから成る群から選択される。前記ヘテロ芳香環又は環系は、好ましくは１つ以上の酸感受性の電子供与基及び／又は電子吸引基によって置換される。 Preferably the heteroaromatic ring or ring system is pyrrole, thiophene, furan, imidazole, thiazole, pyrimidine, pyridine, pyrazine, pyridazine, isoxazole, oxazole, indole, isoindole, indolizine, quinoline, isoquinoline, purine, carbazole, dibenzofuran, Acridine, purine, guanine, xanthine, uric acid, benzothiophene, benzofuran, dibenzothiophene, thianthrene, xanthene, phenoxathiin, isoquinoline, phthalazine, 1,8-naphthydrine, quinazoline, quinoxaline, cinnoline, pteridine, perimidine, 1,7- selected from the group consisting of phenanthroline, phenazine, phosphhindole, phthalimide, furazane, and phosphinoline, most preferably pyridine, pyrimidine, furan, and phthalimide. Said heteroaromatic ring or ring system is preferably substituted by one or more acid-sensitive electron-donating and/or electron-withdrawing groups.

本発明の別の実施態様において、芳香環又は環系は、ベンゼン、ペンタレン、インデン、インダン、ナフタレン、１，１'－ビナフタレン、アズレン、ヘプタレン、ビフェニレン、ａｓ－インダセン、ｓ－インダセン、アセナフチレン、フルオレンフェナレン、フェナントレン、アントラセン、フルオランテン、アセフェナントリレン、アセアントリレントリフェニレン、ピレンクリセン、ナフタセン、プレイアデン、ピセン、及びペリレン、最も好ましくはベンゼンから成る群から選択される。前記芳香環又は環系は、好ましくは１つ以上の酸感受性の電子供与基及び／又は電子吸引基によって置換される。 In another embodiment of the invention, the aromatic ring or ring system is benzene, pentalene, indene, indane, naphthalene, 1,1'-binaphthalene, azulene, heptalene, biphenylene, as-indacene, s-indacene, acenaphthylene, fluorene. selected from the group consisting of phenalene, phenanthrene, anthracene, fluoranthene, acephenanthrylene, aceantrylenetriphenylene, pyrenechrysene, naphthacene, pleiadene, picene, and perylene, most preferably benzene. Said aromatic ring or ring system is preferably substituted by one or more acid-sensitive electron-donating and/or electron-withdrawing groups.

好ましくは、本発明の方法における化合物（Ｉ）は化合物（Ｉａ）である。

Figure 0007397075000007
Preferably, compound (I) in the method of the invention is compound (Ia).
Figure 0007397075000007

式（Ｉａ）の化合物は、例えば定量的１工程法で、濃硝酸と無水酢酸を周囲温度で市販のＮ－サッカリンと反応させることにより調製することができる。式（Ｉａ）の化合物は、保存安定性のある白色の結晶性粉末であり、大規模に調製することができるる。 Compounds of formula (Ia) can be prepared, for example, in a quantitative one-step process by reacting concentrated nitric acid and acetic anhydride with commercially available N-saccharin at ambient temperature. The compound of formula (Ia) is a white crystalline powder that is storage stable and can be prepared on a large scale.

あるいは、本発明の方法における化合物（Ｉ）は化合物（Ｉｂ）である。

Figure 0007397075000008
Alternatively, compound (I) in the method of the present invention is compound (Ib).
Figure 0007397075000008

電子吸引性ＮＯ2基が存在するため、式（Ｉｂ）の化合物は非常に強力であり、ニトロ化反応を強力に加速して、１時間以内にニトロ化生成物を与える。 Due to the presence of the electron-withdrawing NO 2 group, compounds of formula (Ib) are very potent and strongly accelerate the nitration reaction to give the nitrated product within 1 hour.

好ましくは反応は、ヘキサフルオロイソプロパノール、アセトニトリル、ニトロメタン、塩化メチレン、トリフルオロエタノール、テトラヒドロフラン、ヘキサン、ベンゼン、及びトルエン、又はこれらの混合物、好ましくはヘキサフルオロイソプロパノール及びアセトニトリルから成る群から選択される溶媒中で実施される。理論に拘束されることを望まないが、ヘキサフルオロイソプロパノールはニトロ化反応を触媒すると想定される。 Preferably the reaction is carried out in a solvent selected from the group consisting of hexafluoroisopropanol, acetonitrile, nitromethane, methylene chloride, trifluoroethanol, tetrahydrofuran, hexane, benzene, and toluene, or mixtures thereof, preferably hexafluoroisopropanol and acetonitrile. It will be carried out in Without wishing to be bound by theory, it is assumed that hexafluoroisopropanol catalyzes the nitration reaction.

本発明の方法は、触媒の非存在下で実施することができる。しかしながら、反応時間を改善するために、触媒の存在下で反応を実施することは可能である。そのような触媒は、好ましくはプロトン供与酸又はルイス酸である。触媒量は、典型的には５～１５モル％であり、最も好ましくは１０モル％である。 The process of the invention can be carried out in the absence of a catalyst. However, it is possible to carry out the reaction in the presence of a catalyst in order to improve the reaction time. Such catalysts are preferably proton-donating acids or Lewis acids. The amount of catalyst is typically 5 to 15 mole %, most preferably 10 mole %.

本発明の方法において触媒量で使用されるプロトン供与酸は、好ましくは、酢酸、トリメチル酢酸、トリクロロ酢酸、トリフルオロ酢酸、安息香酸、及びこれらの混合物、好ましくは酢酸及びトリメチル酢酸から成る群から選択される。 The proton-donating acid used in catalytic amounts in the process of the invention is preferably selected from the group consisting of acetic acid, trimethylacetic acid, trichloroacetic acid, trifluoroacetic acid, benzoic acid, and mixtures thereof, preferably acetic acid and trimethylacetic acid. be done.

本発明の方法において触媒量で使用されるルイス酸は、好ましくは無機塩であり、最も好ましくは、鉄（ＩＩ）トリフラート、鉄（ＩＩＩ）トリフラート、マグネシウム（ＩＩ）トリフラート、亜鉛（ＩＩ）トリフラート、銅（ＩＩ）トリフラート、臭化鉄（ＩＩ）、臭化鉄（ＩＩＩ）、及び過塩素酸マグネシウム、好ましくは過塩素酸マグネシウムから成る群から選択される。 The Lewis acids used in catalytic amounts in the process of the invention are preferably inorganic salts, most preferably iron(II) triflate, iron(III) triflate, magnesium(II) triflate, zinc(II) triflate, Selected from the group consisting of copper (II) triflate, iron (II) bromide, iron (III) bromide, and magnesium perchlorate, preferably magnesium perchlorate.

好ましくは本発明の方法は、穏やかな条件下で実施される。５０～１００℃、最も好ましくは７０～９０℃、理想的には８５℃の反応温度で、良好な結果を得ることができるであろう。反応時間は、化合物（Ａ）と触媒の存在に強く依存する。通常、反応時間は２時間～２４時間である。 Preferably the method of the invention is carried out under mild conditions. Good results may be obtained with a reaction temperature of 50-100°C, most preferably 70-90°C, ideally 85°C. The reaction time strongly depends on the presence of compound (A) and catalyst. Usually the reaction time is 2 hours to 24 hours.

本発明の方法は、特に酸感受性基が負の影響を受けないので、複雑分子や薬物の後期官能基化を可能にする。これにより、さまざまな分子をより安価で効率的な方法で合成できるため、コストを削減することができる。さらに、これは新しい類似体を作成することを可能にし、従来のアプローチを使用して合成することができなかった新薬の新しい機会を開く。例えば本発明の方法は、ステロイド、イブプロフェン、及び他の生物学的に活性な分子などの多様な官能基を有する複雑分子の後期官能基化を可能にする。従って式（Ｉ）の化合物の独特の安定性及び様々な反応条件とのこれらの適合性のために、式（Ｉ）の化合物は、創薬方法を容易にするであろう。 The method of the invention allows late-stage functionalization of complex molecules and drugs, especially since acid-sensitive groups are not negatively affected. This allows a variety of molecules to be synthesized in a cheaper and more efficient manner, reducing costs. Additionally, this allows new analogs to be created, opening new opportunities for new drugs that could not be synthesized using traditional approaches. For example, the method of the invention allows late-stage functionalization of complex molecules with diverse functional groups such as steroids, ibuprofen, and other biologically active molecules. Therefore, because of the unique stability of compounds of formula (I) and their compatibility with various reaction conditions, compounds of formula (I) will facilitate drug discovery methods.

本発明の方法は、以下のようなニトロ化芳香環又はヘテロ芳香環を含む様々な薬物を調製するために使用することができる。
・ （３，４－ジヒドロキシ－５－ニトロフェニル）（４－メチルフェニル）メタノン（トルカポン）、
・ ５－ニトロ－２－フルアルデヒドセミカルバゾン（ニトロフラール）、
・ Ｄ－（－）－２，２－ジクロロ－Ｎ－（β－ヒドロキシ－α－（ヒドロキシメチル）－ｐ－ニトロフェニルエチル）アセトアミド（クロラムフェニコール）、
・ ３－（５'－ニトロフルフラルアミノ）－２－オキサゾリドン（フラゾリドン）、
・ １－（（５－ニトロ－２－フラニル）メチレン）アミノ－２，４－イミダゾリデンジオン（ニトロフラントイン）、
・ １－［２－（エチルスルホニル）エチル］－２－メチル－５－ニトロ－１Ｈ－イミダゾール（チミダゾール）、
・ １－（２－ヒドロキシ－１－エチル）－２－メチル－５－ニトロイミダゾール（メトロニダゾール）、［７－ニトロ－２－［（プロパン－２－イルアミノ）メチル］－１，２，３，４－テトラヒドロキノリン－６－イル］メタノール（オキサムニキン）、
・ ５－ニトロ－８－ヒドロキシキノリン（ニトロキソリン）、トリニトロフェノール（ピクリン酸）、
・ ４－ニトロフェニルホスフェート、ｐ－ニトロフェノール、２，４－ジニトロフェノール、
・ （６Ｓ）－２－ニトロ－６－［［４－（トリフルオロメトキシ）フェニル］メトキシ］－６，７－ジヒドロ－５Ｈ－イミダゾ［２，１－ｂ］［１，３］オキサジン（プレトマニド）、
・ （２－ブロモエチル）（｛［（２－ブロモエチル）アミノ］［（１－メチル－２－ニトロ－１Ｈ－イミダゾール－５－イル）メトキシ］ホスホリル｝）アミン（エボホスファミド）、
・ ２，２－ジブロモ－Ｎ－［（１Ｒ，２Ｒ）－１，３－ジヒドロキシ－１－（４－ニトロフェニル）プロパン－２－イル］アセトアミド（ブロマムフェニコール）、
・ ４－［（２Ｒ，３Ｒ）－２－（２，２－ジクロロアセトアミド）－３－ヒドロキシ－３－（４－ニトロフェニル）プロポキシ］－４－オキソブタン酸（コハク酸クロラムフェニコール）、
・ ２，２－ジクロロ－Ｎ－［（１Ｒ，２Ｒ）－１，３－ジヒドロキシ－１－（４－メタンスルホニルフェニル）プロパン－２－イル］アセトアミド（チアムフェニコール）、
・ ２－［ベンジル（フェニル）アミノ］エチル５－（５，５－ジメチル－２－オキソ－１，３，２λ5－ジオキサホスフィナン－２－イル）－２，６－ジメチル－４－（３－ニトロフェニル）－１，４－ジヒドロピリジン－３－カルボキシレート（エホニジピン）、
・ １－（４－｛［（２Ｒ）－２－メチル－６－ニトロ－２Ｈ，３Ｈ－イミダゾ［２，１－ｂ］［１，３］オキサゾール－２－イル］メトキシ｝フェニル）－４－［４－（トリフルオロメトキシ）フェノキシ］ピペリジン（デラマニド）、
・ １－メトキシ－３－（２－ニトロ－１Ｈ－イミダゾール－１－イル）プロパン－２－オール（ミソニダゾール）、
・ ３－メチル－４－［（Ｅ）－［（５－ニトロフラン－２－イル）メチリデン］アミノ］－１ラムダ６－チオモルホリン－１，１－ジオン（ニフルチモックス）、
・ １－クロロ－２，４－ジニトロベンゼン（ジニトロクロロベンゼン）、
・ Ｎ－ベンジル－２－（２－ニトロ－１Ｈ－イミダゾール－１－イル）エタニミド酸（ベンズニダゾール）、
・ ４－［２－（５－ニトロ－１Ｈ－イミダゾール－１－イル）エチル］モルホリン（ニモラゾール）、
・ １－メチル－２－｛［４－（メチルスルファニル）フェノキシ］メチル｝－５－ニトロ－１Ｈ－イミダゾール（フェキシニダゾール）、
・ １－（２－ニトロ－１Ｈ－イミダゾール－１－イル）－３－（ピペリジン－１－イル）プロパン－２－オール（ピモニダゾール）、
・ Ｎ－（２－ヒドロキシエチル）－２－（２－ニトロ－１Ｈ－イミダゾール－１－イル）エタニミド酸（エタニダゾール）、
・ １－（２－メチル－５－ニトロ－１Ｈ－イミダゾール－１－イル）プロパン－２－オール（セクニダゾール）、１－クロロ－３－（２－メチル－５－ニトロ－１Ｈ－イミダゾール－１－イル）プロパン－２－オール（オルニダゾール）、
・ Ｎ－［２－（シクロヘキシルオキシ）－４－ニトロフェニル］メタンスルホンアミド（ＮＳ－３９８）及び
・ （２Ｒ，３Ｒ）－２－（２，２－ジクロロアセトアミド）－３－ヒドロキシ－３－（４－ニトロフェニル）プロピルヘキサデカノエート（パルミチン酸クロラムフェニコール）、
・ ２－ニトロ－１－（４－ニトロフェノキシ）－４－（トリフルオロメチル）ベンゼン（フルオロジフェン）、
・ ６－ニトロクマリン、
・ ７－メチル－８－ニトロキノリン、
・ ２－ニトロ－１Ｈ－イミダゾール（アゾマイシン）、
・ １－［２－（エチルスルホニル）エチル］－２－メチル－５－ニトロ－１Ｈ－イミダゾール（チニダゾール）、
・ ５－（１－メチル－５－ニトロ－１Ｈ－イミダゾール－２－イル）－１，３，４－チアジアゾール－２－アミン（メガゾール）、
・ ４－［４－［［２－（４－クロロフェニル）－４，４－ジメチルシクロヘキセン－１－イル］メチル］ピペラジン－１－イル］－Ｎ－［３－ニトロ－４－（オキサン－４－イルメチルアミノ））フェニル］スルホニル－２－（１Ｈ－ピロロ［２，３－ｂ］ピリジン－５－イルオキシ）ベンズアミド（ベントクラックス）、
・ ５－クロロ－Ｎ－（２－クロロ－４－ニトロフェニル）－２－ヒドロキシベンズアミド（ニクロサミド）、
・ （Ｅ）－２－シアノ－３－（３，４－ジヒドロキシ－５－ニトロ－フェニル）－Ｎ、Ｎ－ジエチル－プロプ－２－エンアミド（エンタカポン）、
・ ２－（４－ニトロフェニル）プロパン－２－イル（６－（ベンジルオキシ）－９Ｈ－プリン－２－イル）カルバメート（Ｏ６－ベンジルグアニン誘導体）、
２－（６－ニトロ－４－オキソキノリン－１（４Ｈ）－イル）酢酸エチル（ＦＳＬ－６１）。 The method of the invention can be used to prepare a variety of drugs containing nitrated aromatic or heteroaromatic rings, such as:
・(3,4-dihydroxy-5-nitrophenyl)(4-methylphenyl)methanone (tolcapone),
・5-nitro-2-furaldehyde semicarbazone (nitrofural),
・ D-(-)-2,2-dichloro-N-(β-hydroxy-α-(hydroxymethyl)-p-nitrophenylethyl)acetamide (chloramphenicol),
・3-(5'-nitrofurfuraramino)-2-oxazolidone (furazolidone),
・1-((5-nitro-2-furanyl)methylene)amino-2,4-imidazolidenedione (nitrofurantoin),
・ 1-[2-(ethylsulfonyl)ethyl]-2-methyl-5-nitro-1H-imidazole (thymidazole),
・1-(2-hydroxy-1-ethyl)-2-methyl-5-nitroimidazole (metronidazole), [7-nitro-2-[(propan-2-ylamino)methyl]-1,2,3,4 -tetrahydroquinolin-6-yl]methanol (oxamniquine),
・5-nitro-8-hydroxyquinoline (nitroxoline), trinitrophenol (picric acid),
・4-nitrophenyl phosphate, p-nitrophenol, 2,4-dinitrophenol,
・(6S)-2-nitro-6-[[4-(trifluoromethoxy)phenyl]methoxy]-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (pretomanid) ,
・ (2-bromoethyl)({[(2-bromoethyl)amino][(1-methyl-2-nitro-1H-imidazol-5-yl)methoxy]phosphoryl})amine (evophosfamide),
・2,2-dibromo-N-[(1R,2R)-1,3-dihydroxy-1-(4-nitrophenyl)propan-2-yl]acetamide (bromamphenicol),
・4-[(2R,3R)-2-(2,2-dichloroacetamido)-3-hydroxy-3-(4-nitrophenyl)propoxy]-4-oxobutanoic acid (chloramphenicol succinate),
・2,2-dichloro-N-[(1R,2R)-1,3-dihydroxy-1-(4-methanesulfonylphenyl)propan-2-yl]acetamide (thiamphenicol),
・2-[Benzyl(phenyl)amino]ethyl 5-(5,5-dimethyl-2-oxo-1,3,2λ 5 -dioxaphosphinan-2-yl)-2,6-dimethyl-4-( 3-nitrophenyl)-1,4-dihydropyridine-3-carboxylate (efonidipine),
・ 1-(4-{[(2R)-2-methyl-6-nitro-2H,3H-imidazo[2,1-b][1,3]oxazol-2-yl]methoxy}phenyl)-4- [4-(trifluoromethoxy)phenoxy]piperidine (delamanid),
・1-methoxy-3-(2-nitro-1H-imidazol-1-yl)propan-2-ol (misonidazole),
・3-Methyl-4-[(E)-[(5-nitrofuran-2-yl)methylidene]amino]-1 lambda 6-thiomorpholine-1,1-dione (nifurtimox),
・1-chloro-2,4-dinitrobenzene (dinitrochlorobenzene),
・ N-benzyl-2-(2-nitro-1H-imidazol-1-yl) etanimidic acid (benznidazole),
・4-[2-(5-nitro-1H-imidazol-1-yl)ethyl]morpholine (nimorazole),
・ 1-Methyl-2-{[4-(methylsulfanyl)phenoxy]methyl}-5-nitro-1H-imidazole (fexinidazole),
・ 1-(2-nitro-1H-imidazol-1-yl)-3-(piperidin-1-yl)propan-2-ol (pimonidazole),
・ N-(2-hydroxyethyl)-2-(2-nitro-1H-imidazol-1-yl) etanimidic acid (etanidazole),
・1-(2-methyl-5-nitro-1H-imidazol-1-yl)propan-2-ol (secnidazole), 1-chloro-3-(2-methyl-5-nitro-1H-imidazol-1- il) propan-2-ol (ornidazole),
・ N-[2-(cyclohexyloxy)-4-nitrophenyl]methanesulfonamide (NS-398) and ・ (2R,3R)-2-(2,2-dichloroacetamide)-3-hydroxy-3-( 4-nitrophenyl)propyl hexadecanoate (chloramphenicol palmitate),
・2-nitro-1-(4-nitrophenoxy)-4-(trifluoromethyl)benzene (fluorodifen),
・6-nitrocoumarin,
・7-methyl-8-nitroquinoline,
・2-nitro-1H-imidazole (azomycin),
・ 1-[2-(ethylsulfonyl)ethyl]-2-methyl-5-nitro-1H-imidazole (tinidazole),
・5-(1-methyl-5-nitro-1H-imidazol-2-yl)-1,3,4-thiadiazol-2-amine (megazole),
・4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(oxane-4- ylmethylamino)) phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamide (bentocrax),
・5-chloro-N-(2-chloro-4-nitrophenyl)-2-hydroxybenzamide (niclosamide),
・(E)-2-cyano-3-(3,4-dihydroxy-5-nitro-phenyl)-N,N-diethyl-prop-2-enamide (entacapone),
・2-(4-nitrophenyl)propan-2-yl(6-(benzyloxy)-9H-purin-2-yl)carbamate (O6-benzylguanine derivative),
Ethyl 2-(6-nitro-4-oxoquinolin-1(4H)-yl)acetate (FSL-61).

好適な実施態様において、本発明の方法を使用して式（Ｘ）の化合物が大量に調製される。

Figure 0007397075000009
Figure 0007397075000010
Figure 0007397075000011
Figure 0007397075000012
Figure 0007397075000013
Figure 0007397075000014
Figure 0007397075000015
Figure 0007397075000016
Figure 0007397075000017
Figure 0007397075000018
Figure 0007397075000019
Figure 0007397075000020
 ＴＭＤＯＢは、４，４，５，５－テトラメチル－１，３，２－ジオキサボロラニルを意味する。 In a preferred embodiment, the compound of formula (X) is prepared in large quantities using the method of the invention.
Figure 0007397075000009
Figure 0007397075000010
Figure 0007397075000011
Figure 0007397075000012
Figure 0007397075000013
Figure 0007397075000014
Figure 0007397075000015
Figure 0007397075000016
Figure 0007397075000017
Figure 0007397075000018
Figure 0007397075000019
Figure 0007397075000020
 TMDOB means 4,4,5,5-tetramethyl-1,3,2-dioxaborolanyl.

好ましくは、本発明の方法により得られるニトロ化化合物は、以下の化合物から成る群から選択される。

Figure 0007397075000021
Figure 0007397075000022
Figure 0007397075000023
Figure 0007397075000024
Figure 0007397075000025
Figure 0007397075000026
 Preferably, the nitrated compound obtained by the method of the invention is selected from the group consisting of the following compounds:
Figure 0007397075000021
Figure 0007397075000022
Figure 0007397075000023
Figure 0007397075000024
Figure 0007397075000025
Figure 0007397075000026

本発明のさらなる実施態様は、芳香環又はヘテロ芳香環を含む化合物（Ａ）のニトロ化剤としての、式（Ｉ）の化合物の使用に関する。

Figure 0007397075000027
A further embodiment of the invention relates to the use of compounds of formula (I) as nitration agents for compounds (A) containing aromatic or heteroaromatic rings.
Figure 0007397075000027

（式中、Ｙは水素及びニトロから成る群から選択される）。 (wherein Y is selected from the group consisting of hydrogen and nitro).

実験：
式（Ｉａ）の化合物の合成

Figure 0007397075000028
experiment:
Synthesis of compound of formula (Ia)
Figure 0007397075000028

試薬１の合成の代表的な方法：滴下漏斗、空気出口、及び攪拌棒を備えた２５０ｍＬの三口丸底フラスコに、無水酢酸（２５．７ｍＬ、０．２７ｍｏｌ）中のＮ－サッカリン（１０．０ｇ、５４．６４ｍｍｏｌ）を入れた。溶液を氷浴で０～５℃に冷却し、この溶液に濃硝酸（２５．１ｍＬ、０．６１ｍｏｌ）を３０分間滴加し、乾燥空気を溶液に急速にバブリングして、過剰量の窒素酸化物を除去した。すべての硝酸を加えると、Ｎ－サッカリンは完全に溶解した。冷却浴を取り外し、液体を通して空気を連続的にバブリングしながら、反応混合物を室温で少なくとも４時間撹拌した。反応中に形成された沈殿物を焼結ガラスフィルター上に採取し、高真空下で乾燥させた（１１．８ｇ、収率９５％）。この物質は、高温のクロロホルム又はアセトニトリルから再結晶することができ、白色の結晶性化合物である。分解温度：１８０～１８２℃（質量損失５０％、熱重量分析により測定、ＴＧＡ）；1H-NMR (300 MHz, CD3CN): δ = 8.05 (dt, J = 7.4, 1.5 Hz, 1H), 8.14 (dt, J = 6.1, 1.4 Hz, 1H), 8.16-8.23 (m, 2H); 13C-NMR (75 MHz): δ = 121.7, 123.1, 126.5, 134.4, 135.9, 137.6, 151.7; IR (ATR, ニート): 3097, 1781, 1717, 1601, 1463, 1292, 1176, 1068, 1007, 891, 758, 662, 582, 500; HRMS (EI) m/z C7H4N2O5Sの計算値: [M+] 227.9836, 実測値 227.9842; C7H4N2O5Sの元素分析計算値: C 36.85, H 1.77, N 12.28 実測値: C 36.88, H 1.87, N 12.41. Representative method for the synthesis of Reagent 1: In a 250 mL three-neck round bottom flask equipped with an addition funnel, an air outlet, and a stir bar, N-saccharin (10.0 g) in acetic anhydride (25.7 mL, 0.27 mol) was added. , 54.64 mmol). The solution was cooled to 0-5°C in an ice bath, concentrated nitric acid (25.1 mL, 0.61 mol) was added dropwise to the solution over 30 minutes, and dry air was rapidly bubbled through the solution to remove excess nitrogen oxidation. removed things. Once all the nitric acid was added, the N-saccharin was completely dissolved. The cooling bath was removed and the reaction mixture was stirred at room temperature for at least 4 hours while continuously bubbling air through the liquid. The precipitate formed during the reaction was collected on a sintered glass filter and dried under high vacuum (11.8 g, 95% yield). This material can be recrystallized from hot chloroform or acetonitrile and is a white crystalline compound. Decomposition temperature: 180-182°C (mass loss 50%, measured by thermogravimetric analysis, TGA); 1 H-NMR (300 MHz, CD 3 CN): δ = 8.05 (dt, J = 7.4, 1.5 Hz, 1H) , 8.14 (dt, J = 6.1, 1.4 Hz, 1H), 8.16-8.23 (m, 2H); 13 C-NMR (75 MHz): δ = 121.7, 123.1, 126.5, 134.4, 135.9, 137.6, 151.7; IR (ATR, NEET): 3097, 1781, 1717, 1601, 1463, 1292, 1176, 1068, 1007, 891, 758, 662, 582, 500; HRMS (EI) m/z C 7 H 4 N 2 O 5 S Calculated value for: [M + ] 227.9836, actual value 227.9842; Elemental analysis calculated value for C 7 H 4 N 2 O 5 S: C 36.85, H 1.77, N 12.28 Actual value: C 36.88, H 1.87, N 12.41.

試薬１の無色の結晶は、クロロホルム／アセトニトリル１：１の飽和溶液からゆっくり蒸発させることにより得られた。 Colorless crystals of Reagent 1 were obtained by slow evaporation from a saturated solution of chloroform/acetonitrile 1:1.

式（Ｉｂ）の化合物の合成

Figure 0007397075000029
Synthesis of compound of formula (Ib)
Figure 0007397075000029

試薬２の合成の代表的な方法：滴下漏斗、空気出口、及び攪拌棒を備えた２５０ｍＬの三口丸底フラスコに、無水酢酸（２８．２ｍＬ、０．３０モル）中の６－ニトロサッカリン（１０．０ｇ、３６．６３ｍｍｏｌ）を入れた。溶液を氷浴で０～５℃に冷却し、この溶液に濃硝酸（２８．２ｍＬ、０．６７ｍｏｌ）を３０分間滴加し、乾燥空気を溶液に急速にバブリングして、過剰量の窒素酸化物を除去した。 Representative method for the synthesis of Reagent 2: Into a 250 mL three-neck round bottom flask equipped with an addition funnel, an air outlet, and a stir bar, 6-nitrosaccharin (10 .0g, 36.63mmol) was added. The solution was cooled to 0-5°C in an ice bath, concentrated nitric acid (28.2 mL, 0.67 mol) was added dropwise to the solution for 30 minutes, and dry air was rapidly bubbled through the solution to remove excess nitrogen oxidation. removed things.

すべての硝酸を加えると、６－ニトロサッカリンは完全に溶解した。液体を通して空気を連続的にバブリングしながら、反応混合物を５～１０℃で４時間撹拌した。反応混合物を１０時間冷凍庫に入れて、生成物を完全に沈殿させた。沈殿物を焼結ガラスフィルター上に採取し、冷クロロホルムで洗浄し、高真空下で乾燥させた（９．６ｇ、収率９６％）。生成物は淡黄色（ほぼ白色）の粉末／結晶性化合物である。分解温度：１７４～１７６℃（質量損失５０％、熱重量分析により測定、ＴＧＡ）；1H-NMR (500 MHz, CD3CN): δ= 9.07 (d, J = 2.1 Hz, 1H), 8.76 (dd, J = 8.5, 2.0 Hz, 1H), 8.43 (d, J = 8.4 Hz, 1H); 13C-NMR (125 MHz, CD3CN): δ = 118.3, 127.8, 128.5, 130.6, 135.4, 150.3, 152.9; IR (ATR, ニート): 3073, 1732, 1601, 1529, 1424, 1347, 1180, 1064, 1024, 786, 737, 649, 490; C7H3N3O7Sの元素分析計算値 C 30.78, H 1.11, N 15.38 実測値: C 30.81, H 1.19, N 15.50. When all the nitric acid was added, the 6-nitrosaccharin was completely dissolved. The reaction mixture was stirred at 5-10° C. for 4 hours while continuously bubbling air through the liquid. The reaction mixture was placed in the freezer for 10 hours to completely precipitate the product. The precipitate was collected on a sintered glass filter, washed with cold chloroform, and dried under high vacuum (9.6 g, 96% yield). The product is a pale yellow (almost white) powder/crystalline compound. Decomposition temperature: 174-176°C (mass loss 50%, measured by thermogravimetric analysis, TGA); 1 H-NMR (500 MHz, CD 3 CN): δ= 9.07 (d, J = 2.1 Hz, 1H), 8.76 (dd, J = 8.5, 2.0 Hz, 1H), 8.43 (d, J = 8.4 Hz, 1H); 13C -NMR (125 MHz, CD 3 CN): δ = 118.3, 127.8, 128.5, 130.6, 135.4, 150.3, 152.9; IR (ATR, NEET): 3073, 1732, 1601, 1529, 1424, 1347, 1180, 1064, 1024, 786, 737, 649, 490; Elemental analysis calculation of C 7 H 3 N 3 O 7 S Values C 30.78, H 1.11, N 15.38 Actual values: C 30.81, H 1.19, N 15.50.

試薬２の無色の結晶は、クロロホルム／アセトニトリル１：１の飽和溶液からゆっくり蒸発させることにより得られた。 Colorless crystals of Reagent 2 were obtained by slow evaporation from a saturated solution of 1:1 chloroform/acetonitrile.

試薬１を使用するアレーン類及びヘテロアレーン類のニトロ化 Nitration of arenes and heteroarenes using reagent 1

化合物Ａのニトロ化の代表的な一般方法１：２５ｍＬの容器に試薬１（１．３当量、０．６５ｍｍｏｌ）を入れ、窒素雰囲気下で密封した。アレーン（１．０当量、０．５ｍｍｏｌ）及びＨＦＩＰ（１ｍＬ）を加え、反応混合物を５５～６０℃で３時間加熱した。室温まで冷却した後、溶媒を真空下で除去し、生成物をフラッシュカラムクロマトグラフィー（ＳｉＯ2、酢酸エチル／ｎ－ヘキサン勾配）によって精製した。 Representative General Method for Nitration of Compound A 1: Reagent 1 (1.3 equivalents, 0.65 mmol) was placed in a 25 mL container and sealed under nitrogen atmosphere. Arene (1.0 eq., 0.5 mmol) and HFIP (1 mL) were added and the reaction mixture was heated at 55-60° C. for 3 hours. After cooling to room temperature, the solvent was removed under vacuum and the product was purified by flash column chromatography (SiO 2 , ethyl acetate/n-hexane gradient).

化合物Ａのニトロ化の代表的な一般方法２：２５ ｍＬの容器に試薬１（１．３当量、０．６５ｍｍｏｌ）、Ｍｇ（ＣｌＯ4）2（０．０５ｍｍｏｌ）を入れ、窒素雰囲気下で密封した。アレーン（１．０当量、０．５ｍｍｏｌ）及びＣＨ3ＣＮ（１ｍＬ）を加え、反応混合物を８５℃で５時間加熱した。室温まで冷却した後、溶媒を真空下で除去し、生成物をフラッシュカラムクロマトグラフィー（ＳｉＯ2、酢酸エチル／ｎ－ヘキサン勾配）によって精製した。 Typical general method for nitration of compound A 2: Put reagent 1 (1.3 equivalents, 0.65 mmol) and Mg(ClO 4 ) 2 (0.05 mmol) in a 25 mL container and seal it under nitrogen atmosphere. did. Arene (1.0 eq., 0.5 mmol) and CH 3 CN (1 mL) were added and the reaction mixture was heated at 85° C. for 5 hours. After cooling to room temperature, the solvent was removed under vacuum and the product was purified by flash column chromatography (SiO 2 , ethyl acetate/n-hexane gradient).

表１は、化合物１０１～１４６に言及し、一般方法１又は一般方法２（異性体の総収率）を使用した前記化合物の単独の収率、及び異性体の比率を示す。

Figure 0007397075000030
Figure 0007397075000031
Figure 0007397075000032
Figure 0007397075000033
Figure 0007397075000034
Figure 0007397075000035
Figure 0007397075000036
 Table 1 refers to compounds 101-146 and shows the individual yields of said compounds using General Method 1 or General Method 2 (total yield of isomers) and the ratio of isomers.
Figure 0007397075000030
Figure 0007397075000031
Figure 0007397075000032
Figure 0007397075000033
Figure 0007397075000034
Figure 0007397075000035
Figure 0007397075000036

スペクトルデータ spectral data

ニトロベンゼン（式１０１の化合物）

Figure 0007397075000037

収率 99% （一般的方法１を使用）; 収率 99% （一般的方法２を使用）; 黄色油状物; 1H NMR (300 MHz, クロロホルム-d) δ 8.16 (d, J = 7.6 Hz, 2H), 7.68 (t, J = 7.6 Hz, 1H), 7.52 (m, 2H); 13C NMR (101 MHz, クロロホルム-d) δ 147.88, 134.51, 129.11, 123.24. Nitrobenzene (compound of formula 101)
Figure 0007397075000037
Yield 99% (using general method 1); Yield 99% (using general method 2); yellow oil; 1 H NMR (300 MHz, chloroform-d) δ 8.16 (d, J = 7.6 Hz) , 2H), 7.68 (t, J = 7.6 Hz, 1H), 7.52 (m, 2H); 13 C NMR (101 MHz, chloroform-d) δ 147.88, 134.51, 129.11, 123.24.

１－フルオロ－４－ニトロベンゼン（式１０２の化合物）

Figure 0007397075000038

収率 76.8% （一般的方法１を使用）; 淡黄色固体; mp 109-112 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 8.55 - 8.08 (m, 2H), 7.64 - 6.86 (m, 2H); 13C NMR (75 MHz, クロロホルム-d) δ 166.30 (d, J = 257.9 Hz), 144.43, 126.35 (d, J = 10.0 Hz), 116.44 (d, J = 23.7 Hz); 19F NMR (282 MHz, クロロホルム-d) δ -102.00. 1-fluoro-4-nitrobenzene (compound of formula 102)
Figure 0007397075000038
Yield 76.8% (using general method 1); pale yellow solid; mp 109-112 °C; 1 H NMR (300 MHz, chloroform-d) δ 8.55 - 8.08 (m, 2H), 7.64 - 6.86 (m, 2H); 13 C NMR (75 MHz, chloroform-d) δ 166.30 (d, J = 257.9 Hz), 144.43, 126.35 (d, J = 10.0 Hz), 116.44 (d, J = 23.7 Hz); 19 F NMR (282 MHz, chloroform-d) δ -102.00.

１－（ｔｅｒｔ－ブチル）－４－ニトロベンゼン（式１０３の化合物）

Figure 0007397075000039

収率 84.6% （一般的方法１を使用）; 淡黄色固体; mp 99-102 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 8.50 - 7.99 (m, 2H), 7.86 - 7.34 (m, 2H), 1.36 (s, 9H); 13C NMR (75 MHz, クロロホルム-d) δ 158.88, 145.96, 126.26, 123.37, 35.43, 31.08. 1-(tert-butyl)-4-nitrobenzene (compound of formula 103)
Figure 0007397075000039
Yield 84.6% (using general method 1); pale yellow solid; mp 99-102 °C; 1 H NMR (300 MHz, chloroform-d) δ 8.50 - 7.99 (m, 2H), 7.86 - 7.34 (m, 2H), 1.36 (s, 9H); 13 C NMR (75 MHz, chloroform-d) δ 158.88, 145.96, 126.26, 123.37, 35.43, 31.08.

１－メトキシ－４－ニトロベンゼン（式１０４の化合物）

Figure 0007397075000040

収率 61% （一般的方法１を使用）; 淡黄色固体; mp 52-54 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 8.51 - 8.08 (m, 2H), 7.21 - 6.80 (m, 2H), 3.98 (s, 3H); 13C NMR (75 MHz, クロロホルム-d) δ 164.64, 141.61, 125.94, 114.05, 56.00. 1-methoxy-4-nitrobenzene (compound of formula 104)
Figure 0007397075000040
Yield 61% (using general method 1); pale yellow solid; mp 52-54 °C; 1 H NMR (300 MHz, chloroform-d) δ 8.51 - 8.08 (m, 2H), 7.21 - 6.80 (m, 2H), 3.98 (s, 3H); 13 C NMR (75 MHz, chloroform-d) δ 164.64, 141.61, 125.94, 114.05, 56.00.

１－メチル－４－ニトロベンゼン（式１０５の化合物)

Figure 0007397075000041

収率 49.7% （一般的方法１を使用）; 淡黄色固体; mp 51-53 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 8.09 (d, J = 8.6 Hz, 2H), 7.31 (d, J = 7.4 Hz, 2H), 2.45 (s, 3H); 13C NMR (75 MHz, クロロホルム-d) δ 146.19, 145.99, 129.83, 123.53, 21.62. 1-Methyl-4-nitrobenzene (compound of formula 105)
Figure 0007397075000041
Yield 49.7% (using general method 1); pale yellow solid; mp 51-53 °C; 1 H NMR (300 MHz, chloroform-d) δ 8.09 (d, J = 8.6 Hz, 2H), 7.31 (d , J = 7.4 Hz, 2H), 2.45 (s, 3H); 13 C NMR (75 MHz, chloroform-d) δ 146.19, 145.99, 129.83, 123.53, 21.62.

１－ブロモ－４－ニトロベンゼン（式１０６の化合物)

Figure 0007397075000042

収率 55.2% （一般的方法１を使用）; 黄色固体; mp 123-125 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 8.10 (d, J = 9.0 Hz, 2H), 7.69 (d, J = 9.0 Hz, 2H); 13C NMR (75 MHz, クロロホルム-d) δ 147.09, 132.66, 130.00, 125.04. 1-bromo-4-nitrobenzene (compound of formula 106)
Figure 0007397075000042
Yield 55.2% (using general method 1); yellow solid; mp 123-125 °C; 1 H NMR (300 MHz, chloroform-d) δ 8.10 (d, J = 9.0 Hz, 2H), 7.69 (d, J = 9.0 Hz, 2H); 13 C NMR (75 MHz, chloroform-d) δ 147.09, 132.66, 130.00, 125.04.

(４－ニトロフェニル)(トリフルオロメチル)スルファン（式１０７の化合物)

Figure 0007397075000043

収率 45% (一般的方法１を使用, 19時間); 収率 52.9% （一般的方法２を使用）; 黄色油状物; 1H NMR (400 MHz, クロロホルム-d) δ 8.40 - 8.12 (m, 2H), 7.83 (d, J = 8.7 Hz, 2H); 13C NMR (101 MHz, クロロホルム-d) δ 149.15, 136.08, 132.56 (q, J = 2.0 Hz), 128.94 (q, J = 308.8 Hz), 124.35; 19F NMR (376 MHz, クロロホルム-d) δ -41.34. (4-nitrophenyl)(trifluoromethyl)sulfane (compound of formula 107)
Figure 0007397075000043
Yield 45% (using general method 1, 19 hours); Yield 52.9% (using general method 2); yellow oil; 1 H NMR (400 MHz, chloroform-d) δ 8.40 - 8.12 (m , 2H), 7.83 (d, J = 8.7 Hz, 2H); 13 C NMR (101 MHz, chloroform-d) δ 149.15, 136.08, 132.56 (q, J = 2.0 Hz), 128.94 (q, J = 308.8 Hz ), 124.35; 19 F NMR (376 MHz, chloroform-d) δ -41.34.

１－ヨード－４－ニトロベンゼン（式１０８の化合物)

Figure 0007397075000044

収率 63% （一般的方法１を使用）; 黄色固体; mp 53-55℃; 1H NMR (300 MHz, クロロホルム-d) δ 7.93 (d, J = 9.0 Hz, 2H), 7.92 (d, J = 9.0 Hz, 2H); 13C NMR (75 MHz, クロロホルム-d) δ 147.83, 138.71, 124.88, 102.68. 1-iodo-4-nitrobenzene (compound of formula 108)
Figure 0007397075000044
Yield 63% (using general method 1); yellow solid; mp 53-55°C; 1 H NMR (300 MHz, chloroform-d) δ 7.93 (d, J = 9.0 Hz, 2H), 7.92 (d, J = 9.0 Hz, 2H); 13 C NMR (75 MHz, chloroform-d) δ 147.83, 138.71, 124.88, 102.68.

１－クロロ－４－ニトロベンゼン（式１０９の化合物)

Figure 0007397075000045

収率 57.6% （一般的方法１を使用）; 黄色固体; mp 82-84 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 8.19 (d, J = 9.0 Hz, 2H), 7.52 (d, J = 9.0 Hz, 2H); 13C NMR (75 MHz, クロロホルム-d) δ 146.60, 141.42, 129.62, 124.97. 1-chloro-4-nitrobenzene (compound of formula 109)
Figure 0007397075000045
Yield 57.6% (using general method 1); yellow solid; mp 82-84 °C; 1 H NMR (300 MHz, chloroform-d) δ 8.19 (d, J = 9.0 Hz, 2H), 7.52 (d, J = 9.0 Hz, 2H); 13 C NMR (75 MHz, chloroform-d) δ 146.60, 141.42, 129.62, 124.97.

Ｎ，Ｎ－ジメチル－４－ニトロアニリン（式１１０の化合物)

Figure 0007397075000046

収率 54.6% （一般的方法１を使用）; 黄色固体; mp 162-164 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 8.10 (d, J = 9.4 Hz, 2H), 6.59 (d, J = 9.4 Hz, 2H), 3.10 (s, 6H); 13C NMR (75 MHz, クロロホルム-d) δ 154.26, 136.97, 126.12, 110.26, 40.28. N,N-dimethyl-4-nitroaniline (compound of formula 110)
Figure 0007397075000046
Yield 54.6% (using general method 1); yellow solid; mp 162-164 °C; 1 H NMR (300 MHz, chloroform-d) δ 8.10 (d, J = 9.4 Hz, 2H), 6.59 (d, J = 9.4 Hz, 2H), 3.10 (s, 6H); 13 C NMR (75 MHz, chloroform-d) δ 154.26, 136.97, 126.12, 110.26, 40.28.

１－シクロプロピル－２－ニトロベンゼン（式１１１の化合物)

Figure 0007397075000047

収率 31.3% （一般的方法１を使用）; 白色固体, mp 33-34 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 7.87 (d, J = 8.1 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.43 - 7.29 (m, 1H), 7.23 (d, J = 7.8 Hz, 1H), 2.46 (ddd, J = 13.9, 8.5, 5.4 Hz, 1H), 1.23 - 1.01 (m, 2H), 0.83 - 0.70 (m, 2H); 13C NMR (75 MHz, クロロホルム-d) δ 151.25, 138.05, 132.57, 127.96, 126.41, 124.08, 12.51, 8.08. 1-cyclopropyl-2-nitrobenzene (compound of formula 111)
Figure 0007397075000047
Yield 31.3% (using general method 1); white solid, mp 33-34 °C; 1 H NMR (300 MHz, chloroform-d) δ 7.87 (d, J = 8.1 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.43 - 7.29 (m, 1H), 7.23 (d, J = 7.8 Hz, 1H), 2.46 (ddd, J = 13.9, 8.5, 5.4 Hz, 1H), 1.23 - 1.01 (m , 2H), 0.83 - 0.70 (m, 2H); 13 C NMR (75 MHz, chloroform-d) δ 151.25, 138.05, 132.57, 127.96, 126.41, 124.08, 12.51, 8.08.

２－ニトロ－１，１'－ビフェニル（式１１２の化合物)

Figure 0007397075000048

収率 59.4% （一般的方法１を使用）; 黄色固体; mp 36-38 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 7.86 (d, J = 8.0 Hz, 1H), 7.62 (td, J = 7.5, 1.1 Hz, 1H), 7.55 - 7.38 (m, 5H), 7.38 - 7.29 (m, 2H); 13C NMR (75 MHz, クロロホルム-d) δ 149.39, 137.44, 136.40, 132.29, 132.00, 128.72, 128.27, 128.19, 127.94, 124.10. 2-nitro-1,1'-biphenyl (compound of formula 112)
Figure 0007397075000048
Yield 59.4% (using general method 1); yellow solid; mp 36-38 °C; 1 H NMR (300 MHz, chloroform-d) δ 7.86 (d, J = 8.0 Hz, 1H), 7.62 (td, 13 C NMR (75 MHz, chloroform-d) δ 149.39, 137.44, 136.40, 132.29, 132.00, 128.72, 128.27, 128.19, 127.94, 124.10.

３－ニトロ安息香酸メチル（式１１３の化合物)

Figure 0007397075000049

収率 69.6% （一般的方法２を使用）; 黄色結晶性化合物; mp 77-79 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 8.86 (t, J = 2.0 Hz, 1H), 8.39 (ddt, J = 14.1, 7.8, 1.3 Hz, 2H), 7.65 (t, J = 8.0 Hz, 1H), 3.99 (s, 3H); 13C NMR (75 MHz, クロロホルム-d) δ 164.99, 148.34, 135.29, 131.93, 129.66, 127.42, 124.65, 52.83. Methyl 3-nitrobenzoate (compound of formula 113)
Figure 0007397075000049
Yield 69.6% (using general method 2); yellow crystalline compound; mp 77-79 °C; 1 H NMR (300 MHz, chloroform-d) δ 8.86 (t, J = 2.0 Hz, 1H), 8.39 ( 13 C NMR (75 MHz, chloroform-d) δ 164.99, 148.34, 135.29 , 131.93, 129.66, 127.42, 124.65, 52.83.

３－ニトロベンゾニトリル（式１１４の化合物)

Figure 0007397075000050

収率 81% (一般的方法１を使用, 19時間); 収率 92% （一般的方法２を使用）; 黄色固体; 115-117 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 8.53 (t, J = 1.9 Hz, 1H), 8.48 (ddd, J = 8.3, 2.4, 1.2 Hz, 1H), 8.00 (dt, J = 7.7, 1.4 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H); 13C NMR (75 MHz, クロロホルム-d) δ 148.30, 137.64, 130.72, 127.57, 127.27, 116.57, 114.19. 3-nitrobenzonitrile (compound of formula 114)
Figure 0007397075000050
Yield 81% (using general method 1, 19 hours); Yield 92% (using general method 2); yellow solid; 115-117 °C; 1 H NMR (300 MHz, chloroform-d) δ 8.53 (t, J = 1.9 Hz, 1H), 8.48 (ddd, J = 8.3, 2.4, 1.2 Hz, 1H), 8.00 (dt, J = 7.7, 1.4 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H); 13 C NMR (75 MHz, chloroform-d) δ 148.30, 137.64, 130.72, 127.57, 127.27, 116.57, 114.19.

１－ニトロ－３－(トリフルオロメチル)ベンゼン（式１１５の化合物)

Figure 0007397075000051

収率 59.8% (一般的方法１を使用, 19時間); 黄色油状物; 収率 72% （一般的方法２を使用）; 1H NMR (300 MHz, クロロホルム-d) δ 8.50 (d, J = 1.9 Hz, 1H), 8.44 (dd, J = 8.3, 2.2 Hz, 1H), 7.98 (d, J = 7.8 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H); 13C NMR (75 MHz, クロロホルム-d) δ 148.33, 132.36 (q, J = 34.1 Hz), 131.15 (q, J = 3.5 Hz), 130.37, 126.69 (d, J = 0.75 Hz), 122.73 (q, J = 270.7 Hz), 120.87 (q, J = 3.9 Hz); 19F NMR (282 MHz, クロロホルム-d) δ -62.95. 1-nitro-3-(trifluoromethyl)benzene (compound of formula 115)
Figure 0007397075000051
Yield 59.8% (using general method 1, 19 hours); yellow oil; yield 72% (using general method 2); 1 H NMR (300 MHz, chloroform-d) δ 8.50 (d, J 13 C NMR (75 MHz, chloroform-d) δ 148.33, 132.36 (q, J = 34.1 Hz), 131.15 (q, J = 3.5 Hz), 130.37, 126.69 (d, J = 0.75 Hz), 122.73 (q, J = 270.7 Hz) , 120.87 (q, J = 3.9 Hz); 19 F NMR (282 MHz, chloroform-d) δ -62.95.

２－フルオロ－５－ニトロベンズアルデヒド（式１１６の化合物)

Figure 0007397075000052

収率 75% (一般的方法１を使用, 19時間); 収率 84% （一般的方法２を使用）; 薄い橙色固体; mp 58-60℃; 1H NMR (300 MHz, クロロホルム-d) δ 10.37 (s, 1H), 8.74 (dd, J = 5.9, 2.9 Hz, 1H), 8.49 (ddd, J = 9.0, 4.4, 2.9 Hz, 1H), 7.40 (t, J = 9.0 Hz, 1H); 13C NMR (75 MHz, クロロホルム-d) δ 184.84 (d, J = 5.9 Hz), 167.30 (d, J = 268.4 Hz), 144.86, 131.05 (d, J = 11.0 Hz), 124.95 (d, J = 4.1 Hz), 124.63 (d, J = 10.5 Hz), 118.33 (d, J = 23.2 Hz); 19F NMR (282 MHz, クロロホルム-d) δ -111.19 (dt, J = 9.9, 5.2 Hz); IR (ATR, ニート): 3076, 2899, 1693, 1619, 1523, 1470, 1346, 1226, 1070, 934, 744, 547. 2-fluoro-5-nitrobenzaldehyde (compound of formula 116)
Figure 0007397075000052
Yield 75% (using general method 1, 19 hours); Yield 84% (using general method 2); pale orange solid; mp 58-60°C; 1 H NMR (300 MHz, chloroform-d) δ 10.37 (s, 1H), 8.74 (dd, J = 5.9, 2.9 Hz, 1H), 8.49 (ddd, J = 9.0, 4.4, 2.9 Hz, 1H), 7.40 (t, J = 9.0 Hz, 1H); 13 C NMR (75 MHz, chloroform-d) δ 184.84 (d, J = 5.9 Hz), 167.30 (d, J = 268.4 Hz), 144.86, 131.05 (d, J = 11.0 Hz), 124.95 (d, J = 19 F NMR (282 MHz, chloroform-d) δ -111.19 (dt, J = 9.9, 5.2 Hz); IR (ATR, NEET): 3076, 2899, 1693, 1619, 1523, 1470, 1346, 1226, 1070, 934, 744, 547.

４－クロロ－２－ニトロ－１－(トリフルオロメトキシ)ベンゼン（式１１７の化合物)

Figure 0007397075000053

収率 57.5% (一般的方法１を使用, 19時間); 無色油状物; 収率 60.6% （一般的方法２を使用）; 1H NMR (500 MHz, クロロホルム-d) δ 7.99 (d, J = 2.5 Hz, 1H), 7.64 (dd, J = 8.9, 2.6 Hz, 1H), 7.42 (dq, J = 8.8, 1.4 Hz, 1H); 13C NMR (126 MHz, クロロホルム-d) δ 142.96, 139.83, 134.22, 133.38, 126.06, 124.50, 120.08 (q, J = 261.4 Hz); 19F NMR (471 MHz, クロロホルム-d) δ -57.75. 4-chloro-2-nitro-1-(trifluoromethoxy)benzene (compound of formula 117)
Figure 0007397075000053
Yield 57.5% (using general method 1, 19 hours); colorless oil; yield 60.6% (using general method 2); 1 H NMR (500 MHz, chloroform-d) δ 7.99 (d, J 13 C NMR (126 MHz, chloroform-d) δ 142.96, 139.83 , 134.22, 133.38, 126.06, 124.50, 120.08 (q, J = 261.4 Hz); 19 F NMR (471 MHz, chloroform-d) δ -57.75.

１，３－ジクロロ－２，４－ジニトロベンゼン（式１１８の化合物)

Figure 0007397075000054

収率 37% (一般的方法１を使用, 19時間); 収率 79% （一般的方法２を使用）; 黄色固体; mp 70-72 ℃; 1H NMR (400 MHz, クロロホルム-d) δ 8.03 (dd, J = 8.9, 1.0 Hz, 1H), 7.65 (dd, J = 8.9, 1.0 Hz, 1H); 13C NMR (101 MHz, クロロホルム-d) δ 149.49, 146.68, 130.94, 129.54, 126.75, 121.51. 1,3-dichloro-2,4-dinitrobenzene (compound of formula 118)
Figure 0007397075000054
Yield 37% (using general method 1, 19 hours); yield 79% (using general method 2); yellow solid; mp 70-72 °C; 1 H NMR (400 MHz, chloroform-d) δ 8.03 (dd, J = 8.9, 1.0 Hz, 1H), 7.65 (dd, J = 8.9, 1.0 Hz, 1H); 13 C NMR (101 MHz, chloroform-d) δ 149.49, 146.68, 130.94, 129.54, 126.75, 121.51.

４－(ｔｅｒｔ－ブチル)－３－ニトロ安息香酸メチル（式１１９の化合物)

Figure 0007397075000055

収率 62.1% (一般的方法１を使用, 19時間); 黄色油状物; 収率 67.2% （一般的方法２を使用）; 1H NMR (400 MHz, クロロホルム-d) δ 8.07 (dd, J = 8.4, 1.9 Hz, 1H), 7.97 (d, J = 1.9 Hz, 1H), 7.64 (d, J = 8.4 Hz, 1H), 3.93 (s, 3H), 1.42 (s, 9H); 13C NMR (101 MHz, クロロホルム-d) δ 164.91, 151.09, 146.21, 131.36, 129.13, 129.02, 125.06, 52.55, 36.12, 30.51. Methyl 4-(tert-butyl)-3-nitrobenzoate (compound of formula 119)
Figure 0007397075000055
Yield 62.1% (using general method 1, 19 hours); yellow oil; yield 67.2% (using general method 2); 1 H NMR (400 MHz, chloroform-d) δ 8.07 (dd, J 13 C NMR (101 MHz, Chloroform-d) δ 164.91, 151.09, 146.21, 131.36, 129.13, 129.02, 125.06, 52.55, 36.12, 30.51.

１，３，５－トリメトキシ－２－ニトロベンゼン（式１２０の化合物)

Figure 0007397075000056

収率 93% （一般的方法１を使用）; 黄色結晶性化合物; mp 151-153 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 6.11 (s, 2H), 3.85 (s, 6H), 3.83 (s, 3H); 13C NMR (75 MHz, クロロホルム-d) δ 162.21, 153.36, 126.56, 90.82, 56.44, 55.75. 1,3,5-trimethoxy-2-nitrobenzene (compound of formula 120)
Figure 0007397075000056
Yield 93% (using general method 1); yellow crystalline compound; mp 151-153 °C; 1 H NMR (300 MHz, chloroform-d) δ 6.11 (s, 2H), 3.85 (s, 6H), 3.83 (s, 3H); 13 C NMR (75 MHz, chloroform-d) δ 162.21, 153.36, 126.56, 90.82, 56.44, 55.75.

２－ブロモ－１，３，５－トリメチル－４－ニトロベンゼン（式１２１の化合物)

Figure 0007397075000057

収率 96% （一般的方法１を使用）; 黄色固体; mp 58-62 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 7.10 (s, 1H), 2.49 (s, 3H), 2.43 (s, 3H), 2.29 (s, 3H); 13C NMR (75 MHz, クロロホルム-d) δ 150.66, 140.61, 130.35, 129.62, 127.67, 125.47, 24.04, 18.95, 17.03. 2-bromo-1,3,5-trimethyl-4-nitrobenzene (compound of formula 121)
Figure 0007397075000057
Yield 96% (using general method 1); yellow solid; mp 58-62 °C; 1 H NMR (300 MHz, chloroform-d) δ 7.10 (s, 1H), 2.49 (s, 3H), 2.43 ( s, 3H), 2.29 (s, 3H); 13 C NMR (75 MHz, chloroform-d) δ 150.66, 140.61, 130.35, 129.62, 127.67, 125.47, 24.04, 18.95, 17.03.

１－ニトロ－４－(トリフルオロメトキシ)ベンゼン（式１２２の化合物)

Figure 0007397075000058

収率 71.2% (一般的方法１を使用, 19時間); 黄色油状物; 収率 79.7% (一般的方法２を使用, 19時間); 1H NMR (300 MHz, クロロホルム-d) δ 8.59 - 8.02 (m, 2H), 7.64 - 7.27 (m, 2H); 13C NMR (75 MHz, クロロホルム-d) δ 153.67 (q, J = 1.6 Hz), 146.02, 125.85, 121.00, 120.20 (q, J = 258.7 Hz); 19F NMR (282 MHz, クロロホルム-d) δ -57.81. 1-nitro-4-(trifluoromethoxy)benzene (compound of formula 122)
Figure 0007397075000058
Yield 71.2% (using general method 1, 19 hours); yellow oil; yield 79.7% (using general method 2, 19 hours); 1 H NMR (300 MHz, chloroform-d) δ 8.59 - 8.02 (m, 2H), 7.64 - 7.27 (m, 2H); 13 C NMR (75 MHz, chloroform-d) δ 153.67 (q, J = 1.6 Hz), 146.02, 125.85, 121.00, 120.20 (q, J = 258.7 Hz); 19 F NMR (282 MHz, chloroform-d) δ -57.81.

４，４，５，５－テトラメチル－２－(３－ニトロフェニル)－１，３，２－ジオキサボロラン（式１２３の化合物)

Figure 0007397075000059

収率 42.6% （一般的方法１を使用）; 黄色固体; mp 73-74 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 8.73 - 8.55 (m, 1H), 8.33 - 8.24 (m, 1H), 8.09 (d, J = 7.3 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 1.36 (s, 12H); 13C NMR (75 MHz, クロロホルム-d) δ 147.90, 140.67, 129.43, 128.76, 125.87, 84.63, 24.91. 4,4,5,5-tetramethyl-2-(3-nitrophenyl)-1,3,2-dioxaborolane (compound of formula 123)
Figure 0007397075000059
Yield 42.6% (using general method 1); yellow solid; mp 73-74 °C; 1 H NMR (300 MHz, chloroform-d) δ 8.73 - 8.55 (m, 1H), 8.33 - 8.24 (m, 1H) ), 8.09 (d, J = 7.3 Hz, 1H), 7.53 (t, J = 7.8 Hz, 1H), 1.36 (s, 12H); 13 C NMR (75 MHz, chloroform-d) δ 147.90, 140.67, 129.43 , 128.76, 125.87, 84.63, 24.91.

(３－ニトロフェニル)(フェニル)メタノン（式１２４の化合物)

Figure 0007397075000060

収率 40.8% (一般的方法１を使用, 19時間); 淡黄色固体; mp 94-96 ℃; 1H NMR (400 MHz, クロロホルム-d) δ 8.62 (t, J = 1.8 Hz, 1H), 8.45 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 8.14 (dt, J = 7.6, 1.2 Hz, 1H), 7.87 - 7.76 (m, 2H), 7.71 (t, J = 7.9 Hz, 1H), 7.66 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 7.7 Hz, 2H), 13C NMR (101 MHz, クロロホルム-d) δ 194.16, 148.09, 139.07, 136.26, 135.44, 133.37, 130.01, 129.64, 128.74, 126.72, 124.72. (3-nitrophenyl)(phenyl)methanone (compound of formula 124)
Figure 0007397075000060
Yield 40.8% (using general method 1, 19 hours); pale yellow solid; mp 94-96 °C; 1 H NMR (400 MHz, chloroform-d) δ 8.62 (t, J = 1.8 Hz, 1H), 8.45 (ddd, J = 8.2, 2.2, 1.0 Hz, 1H), 8.14 (dt, J = 7.6, 1.2 Hz, 1H), 7.87 - 7.76 (m, 2H), 7.71 (t, J = 7.9 Hz, 1H) , 7.66 (T, J = 7.4 Hz, 1h), 7.53 (T, J = 7.7 Hz, 2h), 13 C NMR (101 MHz, Chloroform -D) δ 194.16, 148.09, 139.07, 136.26, 135.44, 133.37, 130.01 , 129.64, 128.74, 126.72, 124.72.

２，６－ジクロロ－３－ニトロピリジン（式１２５の化合物)

Figure 0007397075000061

収率 86% （一般的方法２を使用）; 黄色固体; mp 53-55 ℃; 1H NMR (300 MHz, アセトニトリル-d3) δ 8.36 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.5 Hz, 1H); 13C NMR (75 MHz, アセトニトリル-d3) δ 152.38, 143.54, 142.06, 137.28, 124.26, 116.91. 2,6-dichloro-3-nitropyridine (compound of formula 125)
Figure 0007397075000061
Yield 86% (using general method 2); yellow solid; mp 53-55 °C; 1 H NMR (300 MHz, acetonitrile-d 3 ) δ 8.36 (d, J = 8.4 Hz, 1H), 7.63 (d , J = 8.5 Hz, 1H); 13 C NMR (75 MHz, acetonitrile- d 3 ) δ 152.38, 143.54, 142.06, 137.28, 124.26, 116.91.

２，６－ジメチル－３－ニトロピリジン（式１２６の化合物)

Figure 0007397075000062

収率 82% （一般的方法２を使用）; 黄色固体; mp 36-38 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 8.15 (d, J = 8.3 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 2.80 (s, 3H), 2.59 (s, 3H); 13C NMR (75 MHz, クロロホルム-d) δ 163.02, 153.32, 143.69, 132.87, 121.42, 24.71, 24.06. 2,6-dimethyl-3-nitropyridine (compound of formula 126)
Figure 0007397075000062
Yield 82% (using general method 2); yellow solid; mp 36-38 °C; 1 H NMR (300 MHz, chloroform-d) δ 8.15 (d, J = 8.3 Hz, 1H), 7.14 (d, 13 C NMR (75 MHz, chloroform-d) δ 163.02, 153.32, 143.69, 132.87, 121.42, 24.71, 24.06.

２，４－ジクロロ－５－ニトロピリミジン（式１２７の化合物)

Figure 0007397075000063

収率 76% （一般的方法２を使用）; 黄色固体; 30-32 ℃; 1H NMR (400 MHz, アセトニトリル-d3) δ 9.25 (s, 1H); 13C NMR (101 MHz, アセトニトリル-d3) δ 161.68, 157.53, 155.17, 142.15. 2,4-dichloro-5-nitropyrimidine (compound of formula 127)
Figure 0007397075000063
Yield 76% (using general method 2); yellow solid; 30-32 °C; 1 H NMR (400 MHz, acetonitrile-d 3 ) δ 9.25 (s, 1H); 13 C NMR (101 MHz, acetonitrile-d 3 ) δ 9.25 (s, 1H); d3 ) δ 161.68, 157.53, 155.17, 142.15.

２，４－ジクロロ－６－メチル－５－ニトロピリミジン（式１２８の化合物)

Figure 0007397075000064

収率 77% （一般的方法２を使用）; 黄色固体; mp 50-52 ℃; 1H NMR (300 MHz, アセトニトリル-d3) δ 2.59 (d, J = 1.0 Hz, 3H), 13C NMR (75 MHz, アセトニトリル-d3) δ 164.68, 158.52, 152.68, 143.23.
2,4-dichloro-6-methyl-5-nitropyrimidine (compound of formula 128)
Figure 0007397075000064
Yield 77% (using general method 2); yellow solid; mp 50-52 °C; 1 H NMR (300 MHz, acetonitrile-d 3 ) δ 2.59 (d, J = 1.0 Hz, 3H), 13 C NMR (75 MHz, acetonitrile-d 3 ) δ 164.68, 158.52, 152.68, 143.23.

２－メチル－５－ニトロイソインドリン－１，３－ジオン（式１２９の化合物)

Figure 0007397075000065

収率 86% （一般的方法２を使用）; 黄色固体; mp 179-180 ℃; 1H NMR (300 MHz, アセトニトリル-d3) δ 8.58 (dd, J = 8.1, 1.9 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 3.15 (s, 3H); 13C NMR (75 MHz, アセトニトリル-d3) δ 166.24, 165.99, 151.50, 136.59, 133.41, 129.01, 123.78, 117.58, 23.44. 2-Methyl-5-nitroisoindoline-1,3-dione (compound of formula 129)
Figure 0007397075000065
Yield 86% (using general method 2); yellow solid; mp 179-180 °C; 1 H NMR (300 MHz, acetonitrile- d3 ) δ 8.58 (dd, J = 8.1, 1.9 Hz, 1H), 8.53 (d, J = 2.0 Hz, 1H), 8.03 (d, J = 8.1 Hz, 1H), 3.15 (s, 3H); 13 C NMR (75 MHz, acetonitrile-d 3 ) δ 166.24, 165.99, 151.50, 136.59 , 133.41, 129.01, 123.78, 117.58, 23.44.

１－(２－ニトロフェニル)ピロリジン－２，５－ジオン（式１３０の化合物)

Figure 0007397075000066

収率 51.3% (一般的方法１を使用, 19時間); 収率 51% （一般的方法２を使用）; 黄色固体; mp 157-158 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 8.18 (d, J = 8.2 Hz, 1H), 7.76 (t, J = 7.7 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H), 2.98 (d, J = 15 Hz, 2H), 2.92 (d, J = 15 Hz, 2H); 13C NMR (75 MHz, クロロホルム-d) δ 175.42, 145.29, 134.45, 130.57, 130.23, 126.17, 126.02, 28.90. 1-(2-nitrophenyl)pyrrolidine-2,5-dione (compound of formula 130)
Figure 0007397075000066
Yield 51.3% (using general method 1, 19 hours); Yield 51% (using general method 2); yellow solid; mp 157-158 °C; 1 H NMR (300 MHz, chloroform-d) δ 8.18 (d, J = 8.2 Hz, 1H), 7.76 (t, J = 7.7 Hz, 1H), 7.61 (t, J = 7.9 Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H), 2.98 ( 13 C NMR (75 MHz, chloroform-d) δ 175.42, 145.29, 134.45, 130.57, 130.23, 126.17, 126.02, 28.90.

１－(５－ニトロフラン－２－イル)エタン－１－オン（式１３１の化合物)

Figure 0007397075000067

収率 77% （一般的方法１を使用）; 黄色固体; mp 78-79 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 7.30 (d, J = 3.8 Hz, 1H), 7.20 (d, J = 3.8 Hz, 1H), 2.54 (s, 3H); 13C NMR (75 MHz, クロロホルム-d) δ 186.76, 151.95, 151.55, 116.75, 111.93, 26.32. 1-(5-nitrofuran-2-yl)ethane-1-one (compound of formula 131)
Figure 0007397075000067
Yield 77% (using general method 1); yellow solid; mp 78-79 °C; 1 H NMR (300 MHz, chloroform-d) δ 7.30 (d, J = 3.8 Hz, 1H), 7.20 (d, J = 3.8 Hz, 1H), 2.54 (s, 3H); 13 C NMR (75 MHz, chloroform-d) δ 186.76, 151.95, 151.55, 116.75, 111.93, 26.32.

（Ｒ）－２，２'－ジメトキシ－３－ニトロ－１，１'－ビナフタレン（式１３２の化合物）

Figure 0007397075000068

収率 64% （一般的方法１を使用）; 黄色固体; mp 189-191 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 8.77 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 9.1 Hz, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.87 (dd, J = 9.4, 2.3 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.39 (d, J = 9.0 Hz, 1H), 7.27 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.19 - 7.09 (m, 2H), 6.95 (d, J = 8.5 Hz, 1H), 3.75 (s, 3H), 3.70 (s, 3H); 13C NMR (75 MHz, クロロホルム-d) δ 158.16, 154.95, 143.78, 136.94, 133.68, 131.87, 130.12, 129.23, 128.21, 127.25, 126.78, 126.74, 125.18, 124.65, 123.77, 120.13, 119.75, 117.95, 115.53, 113.89, 56.75, 56.64; IR (ATR, ニート): 3062, 2934, 1616, 1509, 1462, 1334, 1265, 1149, 1060, 828, 743, 595; HRMS (ESI+) C22H18NO4の計算値 (m/z): [M+] 360.1225; 実測値 360.1230. (R)-2,2'-dimethoxy-3-nitro-1,1'-binaphthalene (compound of formula 132)
Figure 0007397075000068
Yield 64% (using general method 1); yellow solid; mp 189-191 °C; 1 H NMR (300 MHz, chloroform-d) δ 8.77 (d, J = 2.3 Hz, 1H), 8.10 (d, J = 9.1 Hz, 1H), 7.94 (d, J = 9.1 Hz, 1H), 7.87 (dd, J = 9.4, 2.3 Hz, 1H), 7.82 (d, J = 8.2 Hz, 1H), 7.52 (d, J = 9.0 Hz, 1H), 7.39 (d, J = 9.0 Hz, 1H), 7.27 (ddd, J = 8.1, 6.8, 1.3 Hz, 1H), 7.19 - 7.09 (m, 2H), 6.95 (d, J = 8.5 Hz, 1H), 3.75 (s, 3H), 3.70 (s, 3H); 13 C NMR (75 MHz, chloroform-d) δ 158.16, 154.95, 143.78, 136.94, 133.68, 131.87, 130.12, 129.23 , 128.21 , 127.25, 126.78, 126.74, 125.18, 124.65, 123.77, 120.13, 119.75, 117.95, 115.53, 113.89, 56.75, 56.64; IR (ATR, NEET): 3062, 2934, 1616, 1509, 1462, 1334, 1265, 1149, 1060, 828, 743, 595; HRMS (ESI+) Calculated value for C 22 H 18 NO 4 (m/z): [M + ] 360.1225; Actual value 360.1230.

１２－ニトロ－１，４（１，４）－ジベンゼンアシクロヘキサファン（式１３３の化合物）

Figure 0007397075000069

収率 94% （一般的方法２を使用）; 黄色固体; mp 155-157 ℃ 1H NMR (500 MHz, クロロホルム-d) δ 7.22 (d, J = 1.9 Hz, 1H), 6.79 (dd, J = 7.8, 1.9 Hz, 1H), 6.66 - 6.60 (m, 2H), 6.57 (qd, J = 7.9, 1.9 Hz, 2H), 6.51 - 6.45 (m, 1H), 4.03 (ddd, J = 13.3, 9.5, 2.0 Hz, 1H), 3.19 (tdt, J = 12.8, 7.2, 3.1 Hz, 4H), 3.12 - 3.02 (m, 2H), 2.90 (ddd, J = 13.3, 10.0, 7.1 Hz, 1H); 13C NMR (126 MHz, クロロホルム-d) δ 149.32, 142.08, 139.80, 139.32, 137.77, 137.35, 136.48, 133.20, 133.13, 132.42, 129.99, 129.57, 36.03, 35.01, 34.83, 34.47; IR (ATR, ニート): 2924, 1602, 1516, 1482, 1330, 1180, 1094, 903, 804, 634, 507. 12-nitro-1,4(1,4)-dibenzeneacyclohexaphane (compound of formula 133)
Figure 0007397075000069
Yield 94% (using general method 2); yellow solid; mp 155-157 °C 1 H NMR (500 MHz, chloroform-d) δ 7.22 (d, J = 1.9 Hz, 1H), 6.79 (dd, J = 7.8, 1.9 Hz, 1H), 6.66 - 6.60 (m, 2H), 6.57 (qd, J = 7.9, 1.9 Hz, 2H), 6.51 - 6.45 (m, 1H), 4.03 (ddd, J = 13.3, 9.5 13 C NMR (126 MHz, Chloroform-d) δ 149.32, 142.08, 139.80, 139.32, 137.77, 137.35, 136.48, 133.20, 133.13, 132.42, 129.99, 129.57, 36.03, 3 5.01, 34.83, 34.47; IR (ATR, NEET): 2924 , 1602, 1516, 1482, 1330, 1180, 1094, 903, 804, 634, 507.

１2－ニトロ-１，４（１，４）－ジベンゼンアシクロヘキサファンの無色結晶は、酢酸エチル／ヘキサン １：１中の飽和溶液からゆっくり蒸発させることにより得られた。

Figure 0007397075000070
Colorless crystals of 1 2 -nitro-1,4(1,4)-dibenzene acyclohexaphane were obtained by slow evaporation from a saturated solution in ethyl acetate/hexane 1:1.
Figure 0007397075000070

１2－ニトロ-１，４（１，４）－ジベンゼンアシクロヘキサファンの結晶データと構造の詳細:

Figure 0007397075000071
Crystal data and structural details of 1 2 -nitro-1,4(1,4)-dibenzene acyclohexaphane:
Figure 0007397075000071

１－ニトロナフタレン（式１３４の化合物)

Figure 0007397075000072

収率 94% （一般的方法１を使用）; 淡黄色固体, mp 56-59 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 8.57 (d, J = 8.7 Hz, 1H), 8.24 (d, J = 7.6 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.73 (ddd, J = 8.6, 6.9, 1.5 Hz, 1H), 7.63 (t, J = 7.5 Hz, 1H), 7.55 (t, J = 7.9 Hz, 1H); 13C NMR (75 MHz, クロロホルム-d) δ 134.68, 134.40, 129.49, 128.64, 127.39, 125.19, 124.18, 124.03, 123.18. 1-nitronaphthalene (compound of formula 134)
Figure 0007397075000072
Yield 94% (using general method 1); pale yellow solid, mp 56-59 °C; 1 H NMR (300 MHz, chloroform-d) δ 8.57 (d, J = 8.7 Hz, 1H), 8.24 (d , J = 7.6 Hz, 1H), 8.12 (d, J = 8.2 Hz, 1H), 7.96 (d, J = 8.2 Hz, 1H), 7.73 (ddd, J = 8.6, 6.9, 1.5 Hz, 1H), 7.63 (T, J = 7.5 Hz, 1h), 7.55 (T, J = 7.9 Hz, 1h); 13 C NMR (75 MHz, Chloroform -D) δ 134.68, 129.40, 129.40, 128.64, 127.39, 125.39, 124.18, 124.03 , 123.18.

９－ニトロアントラセン（式１３５の化合物）

Figure 0007397075000073

収率 92% （一般的方法１を使用）; 黄色固体, mp 145-147 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 8.55 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.93 (dd, J = 8.8, 1.1 Hz, 2H), 7.62 (ddd, J = 8.7, 6.7, 1.3 Hz, 2H), 7.52 (ddd, J = 8.0, 6.7, 1.1 Hz, 2H); 13C NMR (75 MHz, クロロホルム-d) δ 144.30, 130.80, 130.39, 128.89, 128.41, 126.21, 122.68, 121.40. 9-nitroanthracene (compound of formula 135)
Figure 0007397075000073
Yield 92% (using general method 1); yellow solid, mp 145-147 °C; 1 H NMR (300 MHz, chloroform-d) δ 8.55 (s, 1H), 8.02 (d, J = 8.4 Hz, 13 C NMR (75 MHz, chloroform-d) δ 144.30, 130.80, 130.39, 128.89, 128.41, 126.21, 122.68, 121.40.

１－クロロ－４－（（４－クロロフェニル）スルホニル）－２－ニトロベンゼン（式１３６の化合物）

Figure 0007397075000074

収率 72% （一般的方法２を使用）; 白色固体; mp 59-61 ℃; 1H NMR (400 MHz, DMSO-d6) δ 8.68 (d, J = 2.2 Hz, 1H), 8.26 (dd, J = 8.5, 2.3 Hz, 1H), 8.10 - 8.00 (m, 3H), 7.78 - 7.71 (m, 2H); 13C NMR (101 MHz, DMSO-d6) δ 148.39, 141.05, 140.20, 138.79, 134.06, 132.62, 131.42, 130.61, 130.37, 125.39. 1-chloro-4-((4-chlorophenyl)sulfonyl)-2-nitrobenzene (compound of formula 136)
Figure 0007397075000074
Yield 72% (using general method 2); white solid; mp 59-61 °C; 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.68 (d, J = 2.2 Hz, 1H), 8.26 (dd , J = 8.5, 2.3 Hz, 1H), 8.10 - 8.00 (m, 3H), 7.78 - 7.71 (m, 2H); 13 C NMR (101 MHz, DMSO-d 6 ) δ 148.39, 141.05, 140.20, 138.79, 134.06, 132.62, 131.42, 130.61, 130.37, 125.39.

５，６－ジメトキシ－７－ニトロ－２，３－ジヒドロ－１Ｈ－インデン－１－オン（式１３７の化合物）

Figure 0007397075000075

収率 79% (一般的方法１を使用, 19時間); 黄色固体; mp 146-148 ℃; 1H NMR (400 MHz, クロロホルム-d) δ 7.03 (s, 1H), 4.00 (s, 3H), 3.90 (s, 3H), 3.29 - 2.96 (m, 2H), 2.90 - 2.56 (m, 2H); 13C NMR (101 MHz, クロロホルム-d) δ 200.25, 159.33, 152.87, 140.46, 139.90, 120.46, 110.20, 62.50, 56.88, 36.81, 25.90. 5,6-dimethoxy-7-nitro-2,3-dihydro-1H-inden-1-one (compound of formula 137)
Figure 0007397075000075
Yield 79% (using general method 1, 19 hours); yellow solid; mp 146-148 °C; 1 H NMR (400 MHz, chloroform-d) δ 7.03 (s, 1H), 4.00 (s, 3H) , 3.90 (S, 3h), 3.29-2.96 (m, 2H), 2.90-2.56 (m, 2H); 13 C NMR (101 MHz, chloroform -D) δ 200.25, 159.33, 152.87, 140.96, 140.90, 120.46, 120.46, 120.46, 120.46, 120.46, 120.46 110.20, 62.50, 56.88, 36.81, 25.90.

（１３Ｓ）－３－メトキシ－１３－メチル－４－ニトロ－６，７，８，９，１１，１２，１３，１４，１５，１６－デカヒドロ－１７Ｈ－シクロペンタ［ａ］フェナントレン－１７－オン（式１３８の化合物）

Figure 0007397075000076

収率 78% （一般的方法１を使用）; 黄色固体; mp 150-152 ℃; 1H NMR (500 MHz, クロロホルム-d) δ 7.34 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 3.86 (s, 3H), 2.86 - 2.69 (m, 2H), 2.51 (dd, J = 19.1, 8.8 Hz, 1H), 2.42 - 2.35 (m, 1H), 2.30 - 2.21 (m, 1H), 2.15 (dt, J = 18.6, 8.9 Hz, 1H), 2.09 - 2.00 (m, 2H), 1.97 (dd, J = 9.1, 2.6 Hz, 1H), 1.68 - 1.36 (m, 6H), 0.91 (s, 3H); 13C NMR (126 MHz, クロロホルム-d) δ 148.55, 141.67, 133.20, 128.86, 127.63, 109.91, 56.32, 50.16, 47.83, 43.83, 37.52, 35.80, 31.44, 25.96, 25.44, 23.92, 21.52, 13.81; IR (ATR, ニート): 2929, 1729, 1619, 1514, 1450, 1267, 1014, 755; HRMS (ESI+) C19H23NO4の計算値 (m/z): [M-Na+] 352.1515; 実測値 352.1519. (13S)-3-methoxy-13-methyl-4-nitro-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one ( Compound of formula 138)
Figure 0007397075000076
Yield 78% (using general method 1); yellow solid; mp 150-152 °C; 1 H NMR (500 MHz, chloroform-d) δ 7.34 (d, J = 8.8 Hz, 1H), 6.85 (d, J = 8.8 Hz, 1H), 3.86 (s, 3H), 2.86 - 2.69 (m, 2H), 2.51 (dd, J = 19.1, 8.8 Hz, 1H), 2.42 - 2.35 (m, 1H), 2.30 - 2.21 (m, 1H), 2.15 (dt, J = 18.6, 8.9 Hz, 1H), 2.09 - 2.00 (m, 2H), 1.97 (dd, J = 9.1, 2.6 Hz, 1H), 1.68 - 1.36 (m, 6H) ), 0.91 (s, 3H); 13 C NMR (126 MHz, chloroform-d) δ 148.55, 141.67, 133.20, 128.86, 127.63, 109.91, 56.32, 50.16, 47.83, 43.83, 37.52, 35 .80, 31.44, 25.96, 25.44 , 23.92, 21.52, 13.81; IR (ATR, NEET): 2929, 1729, 1619, 1514, 1450, 1267, 1014, 755; HRMS (ESI+) Calculated value of C 19 H 23 NO 4 (m/z): [ M-Na + ] 352.1515; Actual value 352.1519.

３，４－ジメトキシ－５－ニトロベンズアルデヒド（式１３９の化合物）

Figure 0007397075000077

収率 91% （一般的方法１を使用）; 淡黄色固体; mp 61-62 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 10.46 (s, 1H), 7.62 (s, 1H), 7.43 (s, 1H), 4.04 (s, 3H), 4.03 (s, 3H); 13C NMR (75 MHz, クロロホルム-d) δ 187.81, 153.39, 152.58, 144.05, 125.72, 109.95, 107.35, 56.95, 56.89; HRMS (EI) C9H9NO5の計算値 (m/z): [M+] 211.04752; 実測値 211.04744. 3,4-dimethoxy-5-nitrobenzaldehyde (compound of formula 139)
Figure 0007397075000077
Yield 91% (using general method 1); pale yellow solid; mp 61-62 °C; 1 H NMR (300 MHz, chloroform-d) δ 10.46 (s, 1H), 7.62 (s, 1H), 7.43 (s, 1H), 4.04 (s, 3H), 4.03 (s, 3H); 13 C NMR (75 MHz, chloroform-d) δ 187.81, 153.39, 152.58, 144.05, 125.72, 109.95, 107.35, 56.95, 56.8 9; HRMS (EI) Calculated value for C 9 H 9 NO 5 (m/z): [M + ] 211.04752; Actual value 211.04744.

（１ｒ，１'ｓ，４Ｒ，４'Ｒ）－４－（３，４－ジフルオロ－２－ニトロフェニル）－４'－プロピル－１，１'－ビ（シクロヘキサン）（式１４０の化合物）

Figure 0007397075000078

収率 90% （一般的方法１を使用）; 黄色固体; mp 67-69 ℃ 1H NMR (300 MHz, クロロホルム-d) δ 7.66 (dd, J = 9.6, 7.3 Hz, 1H), 7.24 (dd, J = 11.3, 7.6 Hz, 1H), 3.03 (t, J = 11.8 Hz, 1H), 1.97 - 1.68 (m, 9H), 1.47 - 0.78 (m, 20H); 13C NMR (75 MHz, クロロホルム-d) δ 152.76 (dd, J = 256.7, 12.4 Hz), 147.48 (dd, J = 252.0, 14.1 Hz), 145.42 - 144.20 (m), 140.15 (dd, J = 6.2, 4.1 Hz), 116.76 (d, J = 19.1 Hz), 114.27 (dd, J = 21.3, 1.9 Hz), 43.28, 42.88, 39.82, 38.95, 37.64, 34.15, 33.57, 30.10, 29.99, 20.08, 14.45; 19F NMR (282 MHz, クロロホルム-d) δ -128.75 - -128.94 (m), -137.26 (ddd, J = 21.7, 9.7, 7.7 Hz); IR (ATR, ニート): 2916, 2847, 1600, 1529, 1508, 1445, 1356, 1298, 1186, 882, 804, 633; HRMS (EI) C21H28NOF2の計算値 (m/z): [M+] 348.21335; 実測値 348.21286. (1r,1's,4R,4'R)-4-(3,4-difluoro-2-nitrophenyl)-4'-propyl-1,1'-bi(cyclohexane) (compound of formula 140)
Figure 0007397075000078
Yield 90% (using general method 1); yellow solid; mp 67-69 °C 1 H NMR (300 MHz, chloroform-d) δ 7.66 (dd, J = 9.6, 7.3 Hz, 1H), 7.24 (dd , J = 11.3, 7.6 Hz, 1H), 3.03 (t, J = 11.8 Hz , 1H), 1.97 - 1.68 (m, 9H), 1.47 - 0.78 (m, 20H); d) δ 152.76 (dd, J = 256.7, 12.4 Hz), 147.48 (dd, J = 252.0, 14.1 Hz), 145.42 - 144.20 (m), 140.15 (dd, J = 6.2, 4.1 Hz), 116.76 (d, 19 F NMR (2 82 MHz, chloroform-d ) δ -128.75 - -128.94 (m), -137.26 (ddd, J = 21.7, 9.7, 7.7 Hz); IR (ATR, NEET): 2916, 2847, 1600, 1529, 1508, 1445, 1356, 1298, 1186 , 882, 804, 633; Calculated value of HRMS (EI) C 21 H 28 NOF 2 (m/z): [M + ] 348.21335; Actual value 348.21286.

２－（４－イソブチル－３－ニトロフェニル）プロパン酸メチル及び２－（４－イソブチル－２－ニトロフェニル）プロパン酸メチル（式１４１の化合物）

Figure 0007397075000079

２つの化合物の総収率89% (一般的方法１を使用, 19時間); 黄色油状物; 1H NMR (400 MHz, クロロホルム-d) δ 7.80 (d, J = 1.9 Hz, 2.5H), 7.70 (s, 1H), 7.44 (dd, J = 8.0, 2.0 Hz, 2.5H), 7.36 (d, J = 1.1 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2.5H), 4.28 (q, J = 7.2 Hz, 1H), 3.77 (q, J = 7.2 Hz, 2.5H), 3.68 (s, 7.5H), 3.66 (s, 3H), 2.75 (d, J = 7.1 Hz, 5H), 2.53 (d, J = 7.2 Hz, 2H), 1.89 (dt, J = 13.5, 6.8 Hz, 3.5H), 1.58 (d, J = 7.2 Hz, 3H), 1.53 (d, J = 7.3 Hz, 7.5H), 0.91 (dd, J = 6.6, 4.7 Hz, 21H); 13C NMR (101 MHz, クロロホルム-d) δ 174.13, 173.93, 149.91, 148.89, 142.40, 139.78, 135.29, 134.15, 133.05, 132.54, 131.60, 129.48, 125.22, 123.83, 52.42, 52.34, 44.75, 44.58, 41.52, 41.02, 30.08, 29.58, 22.57, 22.36, 18.47, 18.05. IR (ATR, ニート): 2956, 1735, 1527, 1347, 1192, 1166, 1066, 854, 818, 678; HRMS (ESI+) C14H19NNaO4の計算値 (m/z): [M-Na+] 288.1200; 実測値 288.1206. Methyl 2-(4-isobutyl-3-nitrophenyl)propanoate and methyl 2-(4-isobutyl-2-nitrophenyl)propanoate (compounds of formula 141)
Figure 0007397075000079
Total yield of two compounds 89% (using general method 1, 19 hours); yellow oil; 1 H NMR (400 MHz, chloroform-d) δ 7.80 (d, J = 1.9 Hz, 2.5H), 7.70 (s, 1H), 7.44 (dd, J = 8.0, 2.0 Hz, 2.5H), 7.36 (d, J = 1.1 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2.5H), 4.28 (q , J = 7.2 Hz, 1H), 3.77 (q, J = 7.2 Hz, 2.5H), 3.68 (s, 7.5H), 3.66 (s, 3H), 2.75 (d, J = 7.1 Hz, 5H), 2.53 (d, J = 7.2 Hz, 2H), 1.89 (dt, J = 13.5, 6.8 Hz, 3.5H), 1.58 (d, J = 7.2 Hz, 3H), 1.53 (d, J = 7.3 Hz, 7.5H) , 0.91 (dd, J = 6.6, 4.7 Hz, 21H); 13 C NMR (101 MHz, chloroform-d) δ 174.13, 173.93, 149.91, 148.89, 142.40, 139.78, 135.29, 134.15, 133.05 , 132.54, 131.60, 129.48 , 125.22, 123.83, 52.42, 52.34, 44.75, 44.58, 41.52, 41.02, 30.08, 29.58, 22.57, 22.36, 18.47, 18.05. IR (ATR, NEET): 2956, 17 35, 1527, 1347, 1192, 1166, 1066, 854, 818, 678; HRMS (ESI+) Calculated value of C 14 H 19 NNaO 4 (m/z): [M-Na + ] 288.1200; Actual value 288.1206.

（Ｓ）－２－（６－メトキシ－５－ニトロナフタレン－２－イル）プロパン酸（式１４３の化合物）

Figure 0007397075000080

収率 90% （一般的方法１を使用）; 黄色固体; mp 132-134 ℃ 1H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.22 (d, J = 9.2 Hz, 1H), 7.95 (d, J = 1.7 Hz, 1H), 7.69 (d, J = 9.2 Hz, 1H), 7.64 (dd, J = 8.8, 1.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 4.04 (s, 3H), 3.88 (q, J = 7.1 Hz, 1H), 1.47 (d, J = 7.1 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 175.50, 148.61, 138.64, 135.26, 132.94, 130.14, 128.15, 126.80, 124.04, 120.23, 114.82, 57.69, 44.88, 18.65; IR (ATR, ニート): 2945, 1722, 1608, 1518, 1359, 1281, 1214, 1163, 1076, 903, 818, 641; HRMS (ESI+) C14H14NO5の計算値 (m/z): [M+] 276.0868; 実測値 276.0866. (S)-2-(6-methoxy-5-nitronaphthalen-2-yl)propanoic acid (compound of formula 143)
Figure 0007397075000080
Yield 90% (using general method 1); yellow solid; mp 132-134 °C 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.42 (s, 1H), 8.22 (d, J = 9.2 Hz, 1H), 7.95 (d, J = 1.7 Hz, 1H), 7.69 (d, J = 9.2 Hz, 1H), 7.64 (dd, J = 8.8, 1.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 4.04 (s, 3H), 3.88 (q, J = 7.1 Hz, 1H), 1.47 (d, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, DMSO-d 6 ) δ 175.50, 148.61 , 138.64, 135.26, 132.94, 130.14, 128.15, 126.80, 124.04, 120.23, 114.82, 57.69, 44.88, 18.65; IR (ATR, NEET): 2945, 1722, 160 8, 1518, 1359, 1281, 1214, 1163, 1076, 903, 818, 641; HRMS (ESI+) Calculated value for C 14 H 14 NO 5 (m/z): [M + ] 276.0868; Actual value 276.0866.

（Ｒ）－６－メトキシ－２，８－ジメチル－７－ニトロ－２－（（４Ｒ，８Ｒ）－４，８，１２－トリメチルトリデシル）クロマン（式１４４の化合物）

Figure 0007397075000081

収率 75% （一般的方法１を使用）; 黄色油状物; 1H NMR (300 MHz, クロロホルム-d) δ 6.71 (s, 1H), 3.82 (s, 3H), 2.68 (t, J = 6.9 Hz, 2H), 2.19 (s, 3H), 1.77 (h, J = 7.0 Hz, 2H), 1.56 - 1.11 (m, 24H), 0.88 - 0.85 (m, 12H); 13C NMR (75 MHz, クロロホルム-d) δ 145.45, 143.29, 138.88, 129.66, 113.65, 113.16, 75.93, 56.75, 39.46, 39.11, 37.17, 37.14, 37.09, 37.02, 32.53, 32.41, 29.87, 27.71, 24.53, 24.18, 23.60, 22.45, 22.35, 20.64, 19.48, 19.35, 18.07, 16.34; IR (ATR, ニート): 2924, 1529, 1476, 1375, 1239, 1102, 1016, 911, 809; HRMS (ESI+) C28H47NO4の計算値 (m/z): [M+] 461.3500; 実測値 461.3500. (R)-6-methoxy-2,8-dimethyl-7-nitro-2-((4R,8R)-4,8,12-trimethyltridecyl)chroman (compound of formula 144)
Figure 0007397075000081
Yield 75% (using general method 1); yellow oil; 1 H NMR (300 MHz, chloroform-d) δ 6.71 (s, 1H), 3.82 (s, 3H), 2.68 (t, J = 6.9 13 C NMR (75 MHz, chloroform) -d) δ 145.45, 143.29, 138.88, 129.66, 113.65, 113.16, 75.93, 56.75, 39.46, 39.11, 37.17, 37.14, 37.09, 37.02, 32.53, 32.41 , 29.87, 27.71, 24.53, 24.18, 23.60, 22.45, 22.35, IR (ATR, NEET): 2924, 1529, 1476, 1375, 1239, 1102, 1016, 911, 809; HRMS (ESI+) C 28 H 47 NO 4 calculation (m /z): [M + ] 461.3500; Actual value 461.3500.

２－ニトロ－１－（４－ニトロフェノキシ）－４－（トリフルオロメチル）ベンゼン （フルオロジフェン）（式１４５の化合物）

Figure 0007397075000082

収率 82.5% (一般的方法１を使用, 19時間); 黄色固体; mp 94-96 ℃ 1H NMR (300 MHz, クロロホルム-d) δ 8.39 - 8.23 (m, 3H), 7.89 (dd, J = 8.8, 2.2 Hz, 1H), 7.30 (d, J = 8.7 Hz, 1H), 7.20 - 7.08 (m, 2H); 13C NMR (126 MHz, クロロホルム-d) δ 160.62, 151.06, 144.53, 141.82, 133.97 - 130.25 (m), 128.06 (q, J = 34.8 Hz), 126.44, 124.11 (q, J = 3.7 Hz), 123.00, 122.48 (q, J = 273.3 Hz), 118.53; 19F NMR (282 MHz, クロロホルム-d) δ -62.47; IR (ATR, ニート): 2916, 1600, 1586, 1533, 1347, 1322, 1230, 902, 804, 747, 633; HRMS (EI) C13H7N2F3O5の計算値 (m/z): [M+] 328.03016; 実測値 328.03004. 2-nitro-1-(4-nitrophenoxy)-4-(trifluoromethyl)benzene (fluorodifen) (compound of formula 145)
Figure 0007397075000082
Yield 82.5% (using general method 1, 19 hours); yellow solid; mp 94-96 °C 1 H NMR (300 MHz, chloroform-d) δ 8.39 - 8.23 (m, 3H), 7.89 (dd, J 13 C NMR (126 MHz, chloroform-d) δ 160.62, 151.06, 144.53, 141.82, 133.97 - 130.25 (m), 128.06 (q, J = 34.8 Hz), 126.44, 124.11 (q, J = 3.7 Hz), 123.00, 122.48 ( q, J = 273.3 Hz), 118.53; Chloroform-d) δ -62.47; IR (ATR, neat): 2916, 1600, 1586, 1533, 1347, 1322, 1230, 902, 804, 747, 633; HRMS (EI) C 13 H 7 N 2 F 3 O Calculated value of 5 (m/z): [M + ] 328.03016; Actual value 328.03004.

２－ニトロ-1-(４－ニトロフェノキシ)－４－(トリフルオロメチル)ベンゼンの無色結晶は、酢酸エチル／ヘキサン １：１中の飽和溶液からゆっくり蒸発させることにより得られた。

Figure 0007397075000083

Colorless crystals of 2-nitro-1-(4-nitrophenoxy)-4-(trifluoromethyl)benzene were obtained by slow evaporation from a saturated solution in ethyl acetate/hexane 1:1.
Figure 0007397075000083

２－ニトロ-1-(４－ニトロフェノキシ)－４－(トリフルオロメチル)ベンゼンの結晶データと構造の詳細:

Figure 0007397075000084
Crystal data and structural details of 2-nitro-1-(4-nitrophenoxy)-4-(trifluoromethyl)benzene:
Figure 0007397075000084

２－（４－クロロ－２－ニトロフェノキシ）－２－メチルプロパン酸エチル（式１４６の化合物）

Figure 0007397075000085

収率 98% （一般的方法１を使用）; 淡黄色油状物; 1H NMR (300 MHz, クロロホルム-d) δ 7.74 (d, J = 2.5 Hz, 1H), 7.39 (dd, J = 9.0, 2.5 Hz, 1H), 6.95 (d, J = 9.0 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 1.64 (s, 6H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR (75 MHz, クロロホルム-d) δ 173.22, 147.58, 143.27, 132.82, 127.16, 125.16, 121.43, 82.10, 61.94, 25.09, 14.09; IR (ATR, ニート): 2988, 1735, 1604, 1531, 1478, 1384, 1354, 1281, 1176, 1100, 1019, 882, 843, 655; HRMS (ESI+) C12H14NO5ClNaの計算値 (m/z): [M-Na+] 310.0449; 実測値 310.0453. Ethyl 2-(4-chloro-2-nitrophenoxy)-2-methylpropanoate (compound of formula 146)
Figure 0007397075000085
Yield 98% (using general method 1); pale yellow oil; 1 H NMR (300 MHz, chloroform-d) δ 7.74 (d, J = 2.5 Hz, 1H), 7.39 (dd, J = 9.0, 13 C NMR (75 MHz, chloroform-d) δ 173.22, 147.58, 143.27, 132.82, 127.16, 125.16, 121.43, 82.10, 61.94, 25.09, 14.09; IR (ATR, neat): 2988, 173 5, 1604, 1531, 1478, 1384, 1354, 1281, 1176, 1100, 1019, 882, 843, 655; Calculated value of HRMS (ESI+) C 12 H 14 NO 5 ClNa (m/z): [M-Na + ] 310.0449; Actual value 310.0453.

２－（ジエチルアミノ）－Ｎ－（２，６－ジメチル－３－ニトロフェニル）アセトアミド（式１４７の化合物）

Figure 0007397075000086

収率 71% (一般的方法１を使用, 19時間); 黄色油状物; 1H NMR (400 MHz, クロロホルム-d) δ 9.08 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.20 (d, J = 8.4 Hz, 1H), 3.24 (s, 2H), 2.71 (q, J = 7.1 Hz, 4H), 2.38 (s, 3H), 2.29 (s, 3H), 1.14 (t, J = 7.1 Hz, 6H); 13C NMR (101 MHz, クロロホルム-d) δ 170.52, 148.99, 141.23, 135.91, 130.72, 128.15, 123.01, 57.38, 48.97, 19.21, 14.87, 12.58. IR (ATR, ニート): 3260, 2969, 1673, 1518, 1485, 1343, 1290, 1203, 1088, 824, 747, 503; HRMS (ESI+) C14H22N3O3の計算値 (m/z): [M+] 280.1652; 実測値 280.1656. 2-(diethylamino)-N-(2,6-dimethyl-3-nitrophenyl)acetamide (compound of formula 147)
Figure 0007397075000086
Yield 71% (using general method 1, 19 hours); yellow oil; 1 H NMR (400 MHz, chloroform-d) δ 9.08 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H) , 7.20 (d, J = 8.4 Hz, 1H), 3.24 (s, 2H), 2.71 (q, J = 7.1 Hz, 4H), 2.38 (s, 3H), 2.29 (s, 3H), 1.14 (t, J = 7.1 Hz, 6H); 13 C NMR (101 MHz, chloroform-d) δ 170.52, 148.99, 141.23, 135.91, 130.72, 128.15, 123.01, 57.38, 48.97, 19.21, 14.87, 12 .58. IR (ATR, NEET) Calculated value of HRMS (ESI+) C 14 H 22 N 3 O 3 (m/z): [M + ] 280.1652; Actual value 280.1656.

１－シクロプロピル－４－ニトロベンゼン（式１４８の化合物)

Figure 0007397075000087

収率 65.7% （一般的方法１を使用）; 淡黄色油状物; 1H NMR (300 MHz, クロロホルム-d) δ 8.42 - 7.91 (m, 2H), 7.26 - 6.96 (m, 2H), 2.24 - 1.74 (m, 1H), 1.27 - 1.03 (m, 2H), 0.94 - 0.69 (m, 2H); 13C NMR (75 MHz, クロロホルム-d) δ 152.64, 145.88, 125.97, 123.67, 15.89, 11.04. 1-cyclopropyl-4-nitrobenzene (compound of formula 148)
Figure 0007397075000087
Yield 65.7% (using general method 1); pale yellow oil; 1 H NMR (300 MHz, chloroform-d) δ 8.42 - 7.91 (m, 2H), 7.26 - 6.96 (m, 2H), 2.24 - 1.74 (m, 1H), 1.27 - 1.03 (m, 2H), 0.94 - 0.69 (m, 2H); 13 C NMR (75 MHz, chloroform-d) δ 152.64, 145.88, 125.97, 123.67, 15.89, 11.04.

１－フルオロ－２－ニトロベンゼン（式１４９の化合物)

Figure 0007397075000088

収率 19.2% （一般的方法１を使用）; 黄色油状物; 1H NMR (300 MHz, クロロホルム-d) δ 8.23 - 8.05 (m, 1H), 7.76 - 7.60 (m, 1H), 7.54 - 7.25 (m, 2H); 13C NMR (75 MHz, クロロホルム-d) δ 155.60 (d, J = 264.8 Hz), 137.55, 135.63 (d, J = 8.6 Hz), 126.16 (d, J = 2.8 Hz), 124.61 (d, J = 4.4 Hz), 118.47 (d, J = 20.6 Hz); 19F NMR (282 MHz, クロロホルム-d) δ -117.65. 1-fluoro-2-nitrobenzene (compound of formula 149)
Figure 0007397075000088
Yield 19.2% (using general method 1); yellow oil; 1 H NMR (300 MHz, chloroform-d) δ 8.23 - 8.05 (m, 1H), 7.76 - 7.60 (m, 1H), 7.54 - 7.25 (m, 2H); 13 C NMR (75 MHz, chloroform-d) δ 155.60 (d, J = 264.8 Hz), 137.55, 135.63 (d, J = 8.6 Hz), 126.16 (d, J = 2.8 Hz), 124.61 (d, J = 4.4 Hz), 118.47 (d, J = 20.6 Hz); 19 F NMR (282 MHz, chloroform-d) δ -117.65.

１－（ｔｅｒｔ－ブチル）－２－ニトロベンゼン（式１５０の化合物）

Figure 0007397075000089

収率 9.4% （一般的方法１を使用）; 黄色油状物; 1H NMR (300 MHz, クロロホルム-d) δ 7.58 - 7.44 (m, 1H), 7.36 (ddd, J = 8.2, 6.3, 2.4 Hz, 1H), 7.30 - 7.12 (m, 2H), 1.34 (s, 9H); 13C NMR (75 MHz, クロロホルム-d) δ 151.34, 141.30, 130.76, 128.62, 126.87, 123.91, 35.71, 30.72. 1-(tert-butyl)-2-nitrobenzene (compound of formula 150)
Figure 0007397075000089
Yield 9.4% (using general method 1); yellow oil; 1 H NMR (300 MHz, chloroform-d) δ 7.58 - 7.44 (m, 1H), 7.36 (ddd, J = 8.2, 6.3, 2.4 Hz , 1H), 7.30 - 7.12 (m, 2H), 1.34 (s, 9H); 13 C NMR (75 MHz, chloroform-d) δ 151.34, 141.30, 130.76, 128.62, 126.87, 123.91, 35.71, 30.72.

１－メトキシ－２－ニトロベンゼン（式１５１の化合物)

Figure 0007397075000090

収率 33% （一般的方法１を使用）; 黄色油状物; 1H NMR (300 MHz, クロロホルム-d) δ 7.83 (dd, J = 8.1, 1.7 Hz, 1H), 7.54 (ddd, J = 8.4, 7.4, 1.7 Hz, 1H), 7.20 - 6.92 (m, 2H), 3.95 (s, 3H); 13C NMR (75 MHz, クロロホルム-d) δ 153.00, 134.23, 125.70, 120.31, 113.56, 56.52. 1-methoxy-2-nitrobenzene (compound of formula 151)
Figure 0007397075000090
Yield 33% (using general method 1); yellow oil; 1 H NMR (300 MHz, chloroform-d) δ 7.83 (dd, J = 8.1, 1.7 Hz, 1H), 7.54 (ddd, J = 8.4 , 7.4, 1.7 Hz, 1H), 7.20 - 6.92 (m, 2H), 3.95 (s, 3H); 13 C NMR (75 MHz, chloroform-d) δ 153.00, 134.23, 125.70, 120.31, 113.56, 56.52.

１－メチル－２－ニトロベンゼン（式１５２の化合物)

Figure 0007397075000091

収率 45.3% （一般的方法１を使用）; 黄色油状物; 1H NMR (300 MHz, クロロホルム-d) δ 7.95 (d, J = 8.2 Hz, 1H), 7.49 (t, J = 7.4 Hz, 1H), 7.40 - 7.27 (m, 2H), 2.59 (s, 3H); 13C NMR (75 MHz, クロロホルム-d) δ 149.32, 133.54, 133.01, 132.77, 126.90, 124.63, 20.39. 1-Methyl-2-nitrobenzene (compound of formula 152)
Figure 0007397075000091
Yield 45.3% (using general method 1); yellow oil; 1 H NMR (300 MHz, chloroform-d) δ 7.95 (d, J = 8.2 Hz, 1H), 7.49 (t, J = 7.4 Hz, 1H), 7.40 - 7.27 (m, 2H), 2.59 (s, 3H); 13 C NMR (75 MHz, chloroform-d) δ 149.32, 133.54, 133.01, 132.77, 126.90, 124.63, 20.39.

４－ニトロ－１，１'－ビフェニル（式１５３の化合物)

Figure 0007397075000092

収率 39.6% （一般的方法１を使用）; 黄色固体; mp 113-114 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 8.30 (d, J = 8.8 Hz, 2H), 7.74 (d, J = 8.8 Hz, 2H), 7.69 - 7.58 (m, 2H), 7.58 - 7.39 (m, 3H); 13C NMR (75 MHz, クロロホルム-d) δ 147.68, 147.15, 138.84, 129.19, 128.95, 127.84, 127.43, 124.15. 4-nitro-1,1'-biphenyl (compound of formula 153)
Figure 0007397075000092
Yield 39.6% (using general method 1); yellow solid; mp 113-114 °C; 1 H NMR (300 MHz, chloroform-d) δ 8.30 (d, J = 8.8 Hz, 2H), 7.74 (d, 13 C NMR (75 MHz, chloroform-d) δ 147.68, 147.15, 138.84, 129.19, 128.95, 127.84, 127.43, 124.15.

４，４，５，５－テトラメチル－２－（２－ニトロフェニル）－１，３，２－ジオキサボロラン（式１５４の化合物）

Figure 0007397075000093

収率 38.4% （一般的方法１を使用）; 橙色油状物; 1H NMR (300 MHz, クロロホルム-d) δ 8.14 (d, J = 8.1 Hz, 1H), 7.71 - 7.60 (m, 1H), 7.60 - 7.46 (m, 2H), 1.42 (s, 12H); 13C NMR (75 MHz, クロロホルム-d) δ 151.01, 133.75, 132.88, 130.08, 123.00, 84.65, 24.77. 4,4,5,5-tetramethyl-2-(2-nitrophenyl)-1,3,2-dioxaborolane (compound of formula 154)
Figure 0007397075000093
Yield 38.4% (using general method 1); orange oil; 1 H NMR (300 MHz, chloroform-d) δ 8.14 (d, J = 8.1 Hz, 1H), 7.71 - 7.60 (m, 1H), 7.60 - 7.46 (m, 2H), 1.42 (s, 12H); 13 C NMR (75 MHz, chloroform-d) δ 151.01, 133.75, 132.88, 130.08, 123.00, 84.65, 24.77.

１－ニトロ－２－（トリフルオロメチル）ベンゼン（式１５５の化合物）

Figure 0007397075000094

収率 12.2% (一般的方法１を使用, 19時間); 黄色油状物; 収率 15% （一般的方法２を使用）; 1H NMR (300 MHz, クロロホルム-d) δ 7.95 - 7.78 (m, 2H), 7.80 - 7.67 (m, 2H); 13C NMR (75 MHz, クロロホルム-d) δ 148.26, 133.14, 132.58, 127.97 (q, J = 5.2 Hz), 125.00, 123.81 (q, J = 33.7 Hz), 122.06 (q, J = 271.5 Hz); 19F NMR (282 MHz, クロロホルム-d) δ -60.01. 1-nitro-2-(trifluoromethyl)benzene (compound of formula 155)
Figure 0007397075000094
Yield 12.2% (using general method 1, 19 hours); yellow oil; yield 15% (using general method 2); 1 H NMR (300 MHz, chloroform-d) δ 7.95 - 7.78 (m , 2H), 7.80 - 7.67 (m, 2H); 13 C NMR (75 MHz, chloroform-d) δ 148.26, 133.14, 132.58, 127.97 (q, J = 5.2 Hz), 125.00, 123.81 (q, J = 33.7 Hz), 122.06 (q, J = 271.5 Hz); 19 F NMR (282 MHz, chloroform-d) δ -60.01.

１－ブロモ－２－ニトロベンゼン（式１５６の化合物)

Figure 0007397075000095

収率 36.8% （一般的方法１を使用）; 黄色固体; mp 42-44 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 7.84 (dd, J = 7.5, 2.3 Hz, 1H), 7.75 (dt, J = 8.3, 1.9 Hz, 1H), 7.56 - 7.37 (m, 2H); 13C NMR (75 MHz, クロロホルム-d) δ 149.94, 135.12, 133.21, 128.27, 125.63, 114.51. 1-bromo-2-nitrobenzene (compound of formula 156)
Figure 0007397075000095
Yield 36.8% (using general method 1); yellow solid; mp 42-44 °C; 1 H NMR (300 MHz, chloroform-d) δ 7.84 (dd, J = 7.5, 2.3 Hz, 1H), 7.75 ( dt, J = 8.3, 1.9 Hz, 1H), 7.56 - 7.37 (m, 2H); 13 C NMR (75 MHz, chloroform-d) δ 149.94, 135.12, 133.21, 128.27, 125.63, 114.51.

１－ニトロ－２－（トリフルオロメトキシ）ベンゼン（式１５７の化合物）

Figure 0007397075000096

収率 14.8% (一般的方法１を使用, 19時間); 黄色油状物; 収率 17.3% (一般的方法２を使用, 19時間); 1H NMR (300 MHz, クロロホルム-d) δ 7.99 (dd, J = 8.4, 1.7 Hz, 1H), 7.67 (td, J = 7.8, 1.7 Hz, 1H), 7.56 - 7.39 (m, 2H); 13C NMR (75 MHz, クロロホルム-d) δ 142.85, 141.35 (q, J = 2.0 Hz), 134.25, 127.61, 125.95, 123.26, 120.24 (q, J = 260.6 Hz); 19F NMR (282 MHz, クロロホルム-d) δ -57.58. 1-nitro-2-(trifluoromethoxy)benzene (compound of formula 157)
Figure 0007397075000096
Yield 14.8% (using general method 1, 19 hours); yellow oil; yield 17.3% (using general method 2, 19 hours); 1 H NMR (300 MHz, chloroform-d) δ 7.99 ( 13 C NMR (75 MHz, chloroform-d) δ 142.85, 141.35 (q, J = 2.0 Hz), 134.25, 127.61, 125.95, 123.26, 120.24 (q, J = 260.6 Hz); 19 F NMR (282 MHz, chloroform-d) δ -57.58.

（２－ニトロフェニル）（トリフルオロメチル）スルファン（式１５８の化合物）

Figure 0007397075000097

収率 41% (一般的方法１を使用, 19時間); 収率 44.1% （一般的方法２を使用）; 黄色油状物; 1H NMR (400 MHz, クロロホルム-d) δ 8.12 (dd, J = 8.2, 1.4 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.68 (td, J = 7.8, 1.4 Hz, 1H), 7.55 (td, J = 7.9, 1.2 Hz, 1H); 13C NMR (101 MHz, クロロホルム-d) δ 149.29, 133.70, 132.72 - 131.91 (m), 129.42, 188.66 (q, J = 311.0 Hz), 125.70, 124.37 - 124.06 (m); 19F NMR (376 MHz, クロロホルム-d) δ -41.23. (2-nitrophenyl)(trifluoromethyl)sulfane (compound of formula 158)
Figure 0007397075000097
Yield 41% (using general method 1, 19 hours); Yield 44.1% (using general method 2); yellow oil; 1 H NMR (400 MHz, chloroform-d) δ 8.12 (dd, J 13 19 F NMR (376 MHz) , Chloroform-d) δ -41.23.

１－（４－ニトロフェニル）ピロリジン－２，５－ジオン（式１５９の化合物）

Figure 0007397075000098

収率 42.7% (一般的方法１を使用, 19時間); 収率 46% （一般的方法２を使用）; 黄色固体; mp 208-209 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 8.41 (d, J = 8.9 Hz, 2H), 7.67 (d, J = 8.9 Hz, 2H), 3.03 (s, 4H); 13C NMR (75 MHz, クロロホルム-d) δ 175.35, 147.16, 137.53, 127.00, 124.54, 28.56. 1-(4-nitrophenyl)pyrrolidine-2,5-dione (compound of formula 159)
Figure 0007397075000098
Yield 42.7% (using general method 1, 19 hours); Yield 46% (using general method 2); yellow solid; mp 208-209 °C; 1 H NMR (300 MHz, chloroform-d) δ 8.41 (d, J = 8.9 Hz, 2H), 7.67 (d, J = 8.9 Hz, 2H), 3.03 (s, 4H); 13 C NMR (75 MHz, chloroform-d) δ 175.35, 147.16, 137.53, 127.00 , 124.54, 28.56.

１－クロロ－２－ニトロベンゼン（式１６０の化合物)

Figure 0007397075000099

収率 38.4% （一般的方法１を使用）; 黄色固体; mp 32-33 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 7.87 (dd, J = 8.0, 1.6 Hz, 1H), 7.63 - 7.47 (m, 2H), 7.42 (ddd, J = 8.7, 6.9, 2.0 Hz, 1H); 13C NMR (75 MHz, クロロホルム-d) δ 148.28, 133.16, 131.93, 127.60, 127.13, 125.60. 1-chloro-2-nitrobenzene (compound of formula 160)
Figure 0007397075000099
Yield 38.4% (using general method 1); yellow solid; mp 32-33 °C; 1 H NMR (300 MHz, chloroform-d) δ 7.87 (dd, J = 8.0, 1.6 Hz, 1H), 7.63 - 7.47 (m, 2H), 7.42 (ddd, J = 8.7, 6.9, 2.0 Hz, 1H); 13 C NMR (75 MHz, chloroform-d) δ 148.28, 133.16, 131.93, 127.60, 127.13, 125.60.

Ｎ，Ｎ－ジメチル－２－ニトロアニリン（式１６１の化合物)

Figure 0007397075000100

収率 36.4% （一般的方法１を使用）; 黄色油状物; 1H NMR (300 MHz, クロロホルム-d) δ 8.70 (d, J = 2.7 Hz, 1H), 8.21 (dd, J = 9.5, 2.7 Hz, 1H), 7.01 (d, J = 9.4 Hz, 1H), 3.06 (s, 6H); 13C NMR (75 MHz, クロロホルム-d) δ 149.16, 136.56, 135.85, 127.80, 124.22, 116.63, 42.45. N,N-dimethyl-2-nitroaniline (compound of formula 161)
Figure 0007397075000100
Yield 36.4% (using general method 1); yellow oil; 1 H NMR (300 MHz, chloroform-d) δ 8.70 (d, J = 2.7 Hz, 1H), 8.21 (dd, J = 9.5, 2.7 13 C NMR (75 MHz, chloroform-d) δ 149.16, 136.56, 135.85, 127.80, 124.22, 116.63, 42.45.

（４－ニトロフェニル）（フェニル）メタノン（式１６２の化合物）

Figure 0007397075000101

収率 24.5% (一般的方法１を使用, 19時間); 淡黄色固体; mp 136-139 ℃; 1H NMR (400 MHz, クロロホルム-d) δ 8.35 (d, J = 8.6 Hz, 2H), 7.94 (d, J = 8.6 Hz, 2H), 7.80 (d, J = 8.3 Hz, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 7.8 Hz, 2H); 13C NMR (101 MHz, クロロホルム-d) δ 194.79, 149.84, 142.89, 136.29, 133.47, 130.70, 130.10, 128.69, 123.55. (4-nitrophenyl)(phenyl)methanone (compound of formula 162)
Figure 0007397075000101
Yield 24.5% (using general method 1, 19 hours); pale yellow solid; mp 136-139 °C; 1 H NMR (400 MHz, chloroform-d) δ 8.35 (d, J = 8.6 Hz, 2H), 7.94 (d, J = 8.6 Hz, 2H), 7.80 (d, J = 8.3 Hz, 2H), 7.66 (t, J = 7.4 Hz, 1H), 7.53 (t, J = 7.8 Hz, 2H); 13 C NMR (101 MHz, Chloroform-d) δ 194.79, 149.84, 142.89, 136.29, 133.47, 130.70, 130.10, 128.69, 123.55.

１－クロロ－２－ニトロ－４－（トリフルオロメトキシ）ベンゼン（式１６３の化合物）

Figure 0007397075000102

収率 34.5% (一般的方法１を使用, 19時間); 無色油状物; 収率 36.4% （一般的方法２を使用）; 1H NMR (500 MHz, クロロホルム-d) δ 7.78 (d, J = 2.8 Hz, 1H), 7.62 (d, J = 8.9 Hz, 1H), 7.41 (ddd, J = 8.9, 2.9, 1.0 Hz, 1H); 13C NMR (126 MHz, クロロホルム-d) δ 148.13, 147.46 (q, J = 2.3 Hz), 133.23, 125.65, 125.52, 120.14 (q, J = 260.3 Hz), 118.50; 19F NMR (471 MHz, クロロホルム-d) δ -58.30. 1-chloro-2-nitro-4-(trifluoromethoxy)benzene (compound of formula 163)
Figure 0007397075000102
Yield 34.5% (using general method 1, 19 hours); colorless oil; yield 36.4% (using general method 2); 1 H NMR (500 MHz, chloroform-d) δ 7.78 (d, J 13 C NMR (126 MHz, chloroform-d) δ 148.13, 147.46 (q, J = 2.3 Hz), 133.23, 125.65, 125.52, 120.14 (q, J = 260.3 Hz), 118.50; 19 F NMR (471 MHz, chloroform-d) δ -58.30.

４－（ｔｅｒｔ－ブチル）－２－ニトロ安息香酸メチル（式１６４の化合物）

Figure 0007397075000103

収率 24.9% (一般的方法１を使用, 19時間); 淡黄色油状物; 収率 26.8% （一般的方法２を使用）; 1H NMR (400 MHz, クロロホルム-d) δ 7.86 (d, J = 1.7 Hz, 1H), 7.73 - 7.61 (m, 2H), 3.90 (s, 3H), 1.36 (s, 9H); 13C NMR (101 MHz, クロロホルム-d) δ 165.80, 156.50, 148.64, 129.83, 129.67, 124.30, 120.92, 53.11, 35.39, 30.89. Methyl 4-(tert-butyl)-2-nitrobenzoate (compound of formula 164)
Figure 0007397075000103
Yield 24.9% (using general method 1, 19 hours); pale yellow oil; yield 26.8% (using general method 2); 1 H NMR (400 MHz, chloroform-d) δ 7.86 (d, 13 C NMR (101 MHz, chloroform-d) δ 165.80, 156.50, 148.64, 129.83 , 129.67, 124.30, 120.92, 53.11, 35.39, 30.89.

（２－ニトロフェニル）（フェニル）メタノン（式１６５の化合物）

Figure 0007397075000104

収率 32.7% (一般的方法１を使用, 19時間); 淡黄色固体; mp 104-106 ℃; 1H NMR (400 MHz, クロロホルム-d) δ 8.24 (d, J = 8.2 Hz, 1H), 7.76 (dd, J = 11.4, 8.0 Hz, 3H), 7.68 (t, J = 7.8 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.54 - 7.41 (m, 3H); 13C NMR (101 MHz, クロロホルム-d) δ 193.43, 146.72, 136.24, 135.92, 134.16, 133.82, 130.52, 129.24, 128.91, 128.78, 124.48. (2-nitrophenyl)(phenyl)methanone (compound of formula 165)
Figure 0007397075000104
Yield 32.7% (using general method 1, 19 hours); pale yellow solid; mp 104-106 °C; 1 H NMR (400 MHz, chloroform-d) δ 8.24 (d, J = 8.2 Hz, 1H), 7.76 (dd, J = 11.4, 8.0 Hz, 3H), 7.68 (t, J = 7.8 Hz, 1H), 7.59 (t, J = 7.4 Hz, 1H), 7.54 - 7.41 (m, 3H); 13 C NMR (101 MHz, Chloroform-d) δ 193.43, 146.72, 136.24, 135.92, 134.16, 133.82, 130.52, 129.24, 128.91, 128.78, 124.48.

１－ヨード－２－ニトロベンゼン（式１６６の化合物)

Figure 0007397075000105

収率 30% （一般的方法１を使用）; 黄色油状物; 1H NMR (300 MHz, クロロホルム-d) δ 7.98 (dd, J = 7.9, 1.3 Hz, 1H), 7.79 (dd, J = 8.1, 1.5 Hz, 1H), 7.42 (td, J = 7.8, 1.3 Hz, 1H), 7.33 - 7.11 (m, 1H); 13C NMR (75 MHz, クロロホルム-d) δ 153.13, 141.95, 133.39, 129.08, 125.46, 86.23. 1-iodo-2-nitrobenzene (compound of formula 166)
Figure 0007397075000105
Yield 30% (using general method 1); yellow oil; 1 H NMR (300 MHz, chloroform-d) δ 7.98 (dd, J = 7.9, 1.3 Hz, 1H), 7.79 (dd, J = 8.1 , 1.5 Hz, 1H), 7.42 (td, J = 7.8, 1.3 Hz, 1H), 7.33 - 7.11 (m, 1H); 13 C NMR (75 MHz, chloroform-d) δ 153.13, 141.95, 133.39, 129.08, 125.46, 86.23.

２－ニトロ安息香酸メチル（式１６７の化合物)

Figure 0007397075000106

収率 17.4% （一般的方法２を使用）; 黄色油状物; 1H NMR (300 MHz, クロロホルム-d) δ 7.91 (dd, J = 7.4, 1.9 Hz, 1H), 7.83 - 7.72 (m, 1H), 7.65 (pd, J = 7.4, 1.7 Hz, 2H), 3.92 (s, 3H); 13C NMR (75 MHz, クロロホルム-d) δ 165.89, 148.31, 132.92, 131.79, 129.90, 127.64, 123.96, 53.30. Methyl 2-nitrobenzoate (compound of formula 167)
Figure 0007397075000106
Yield 17.4% (using general method 2); yellow oil; 1 H NMR (300 MHz, chloroform-d) δ 7.91 (dd, J = 7.4, 1.9 Hz, 1H), 7.83 - 7.72 (m, 1H) ), 7.65 (pd, J = 7.4, 1.7 Hz, 2H), 3.92 (s, 3H); 13 C NMR (75 MHz, chloroform-d) δ 165.89, 148.31, 132.92, 131.79, 129.90, 127.64, 123.96, 53 .30 .

（１３Ｓ）－３－メトキシ－１３－メチル－２－ニトロ－６，７，８，９，１１，１２，１３，１４，１５，１６－デカヒドロ－１７Ｈ－シクロペンタ［ａ］フェナントレン－１７－オン（式１６８の化合物）

Figure 0007397075000107

収率 13% （一般的方法１を使用）; 黄色固体; mp 244-248 ℃; 1H NMR (500 MHz, クロロホルム-d) δ 7.84 (s, 1H), 6.80 (s, 1H), 3.94 (s, 3H), 2.97 (p, J = 11.4 Hz, 2H), 2.54 (dd, J = 19.1, 8.7 Hz, 1H), 2.45 - 2.38 (m, 1H), 2.32 - 2.22 (m, 1H), 2.17 (dt, J = 18.7, 8.9 Hz, 1H), 2.12 - 2.05 (m, 2H), 2.01 (d, J = 12.3 Hz, 1H), 1.71 - 1.47 (m, 6H), 0.94 (s, 3H); 13C NMR (126 MHz, クロロホルム-d) δ 151.16, 144.39, 137.36, 132.42, 123.12, 113.58, 56.49, 50.26, 47.87, 43.48, 37.86, 35.79, 31.33, 29.81, 26.07, 25.72, 21.54, 13.81; IR (ATR, ニート): 2917, 1728, 1526, 1491, 1404, 1377, 1282, 1074, 856, 816, 657; HRMS (ESI+) C19H23NO4の計算値 (m/z): [M-Na+] 352.1515; 実測値 352.1519. (13S)-3-Methoxy-13-methyl-2-nitro-6,7,8,9,11,12,13,14,15,16-decahydro-17H-cyclopenta[a]phenanthren-17-one ( Compound of formula 168)
Figure 0007397075000107
Yield 13% (using general method 1); yellow solid; mp 244-248 °C; 1 H NMR (500 MHz, chloroform-d) δ 7.84 (s, 1H), 6.80 (s, 1H), 3.94 ( s, 3H), 2.97 (p, J = 11.4 Hz, 2H), 2.54 (dd, J = 19.1, 8.7 Hz, 1H), 2.45 - 2.38 (m, 1H), 2.32 - 2.22 (m, 1H), 2.17 (dt, J = 18.7, 8.9 Hz, 1H), 2.12 - 2.05 (m, 2H), 2.01 (d, J = 12.3 Hz, 1H), 1.71 - 1.47 (m, 6H), 0.94 (s, 3H); 13 C NMR (126 MHz, Chloroform-d) δ 151.16, 144.39, 137.36, 132.42, 123.12, 113.58, 56.49, 50.26, 47.87, 43.48, 37.86, 35.79, 31.33, 29. 81, 26.07, 25.72, 21.54, 13.81; IR ( ATR, NEET): 2917, 1728, 1526, 1491, 1404, 1377, 1282, 1074, 856, 816, 657; HRMS (ESI+) Calculated value of C 19 H 23 NO 4 (m/z): [M-Na + ] 352.1515; Actual value 352.1519.

２，４－ジニトロ－１－（４－（トリフルオロメチル）フェノキシ）ベンゼン（式１６９の化合物）

Figure 0007397075000108

収率 5.5% (一般的方法１を使用, 19時間); 白色固体; mp 114-116 ℃ 1H NMR (300 MHz, クロロホルム-d) δ 8.91 (d, J = 2.7 Hz, 1H), 8.42 (dd, J = 9.2, 2.7 Hz, 1H), 7.78 (d, J = 8.5 Hz, 2H), 7.31 - 7.24 (m, 2H), 7.16 (d, J = 9.2 Hz, 1H); 13C NMR (75 MHz, クロロホルム-d) δ 156.80, 154.79, 142.59, 140.48, 129.08, 128.68 (d, J = 33.2 Hz), 128.24 (q, J = 3.6 Hz), 123.77 (q, J = 270.7 Hz), 122.35, 120.35, 119.92; 19F NMR (282 MHz, クロロホルム-d) δ -62.23; IR (ATR, ニート): 3095, 1601, 1532, 1508, 1349, 1317, 1270, 1123, 1063, 833, 676, 638; HRMS (EI) C13H7N2F3O5の計算値 (m/z): [M+] 328.03016; 実測値 328.03004. 2,4-dinitro-1-(4-(trifluoromethyl)phenoxy)benzene (compound of formula 169)
Figure 0007397075000108
Yield 5.5% (using general method 1, 19 hours); white solid; mp 114-116 °C 1 H NMR (300 MHz, chloroform-d) δ 8.91 (d, J = 2.7 Hz, 1H), 8.42 ( 13 C NMR (75 MHz, Chloroform-d) δ 156.80, 154.79, 142.59, 140.48, 129.08, 128.68 (d, J = 33.2 Hz), 128.24 (q, J = 3.6 Hz), 123.77 (q, J = 270.7 Hz), 122.35, 120.35 , 119.92; 19 F NMR (282 MHz, chloroform-d) δ -62.23; IR (ATR, neat): 3095, 1601, 1532, 1508, 1349, 1317, 1270, 1123, 1063, 833, 676, 638; HRMS (EI) Calculated value of C 13 H 7 N 2 F 3 O 5 (m/z): [M + ] 328.03016; Actual value 328.03004.

２，６－ジヒドロキシ－３－ニトロ安息香酸（式１７０の化合物）

Figure 0007397075000109

収率 88%, 88 mg （一般的方法Ｉを使用）; 黄色固体; mp 215.5-217.0 ℃; 1H NMR (400 MHz, アセトン-d6) δ 14.95 (s, 1H), 8.00 (d, J = 9.4 Hz, 1H), 6.24 (d, J = 9.4 Hz, 1H), 3.45 (bs, 2H); 13C NMR (101 MHz, アセトン-d6) δ 176.8, 169.7, 162.7, 131.1, 129.4, 106.6, 104.5; IR (ATR, ニート): 3436, 1718, 1595, 1450, 1249, 1145, 922, 824, 755, 590; HRMS (ESI+) C7H4NO6の計算値 (m/z): [M-H] 198.0044; 実測値 198.0049. 2,6-dihydroxy-3-nitrobenzoic acid (compound of formula 170)
Figure 0007397075000109
Yield 88%, 88 mg (using general method I); yellow solid; mp 215.5-217.0 °C; 1 H NMR (400 MHz, acetone-d 6 ) δ 14.95 (s, 1H), 8.00 (d, J = 9.4 Hz, 1H), 6.24 (d, J = 9.4 Hz, 1H), 3.45 (bs, 2H); 13 C NMR (101 MHz, acetone-d 6 ) δ 176.8, 169.7, 162.7, 131.1, 129.4, 106.6 , 104.5; IR (ATR, NEET): 3436, 1718, 1595, 1450, 1249, 1145, 922, 824, 755, 590; HRMS (ESI+) Calculated value of C 7 H 4 NO 6 (m/z): [ MH] 198.0044; Actual value 198.0049.

４－クロロ－３－ニトロフェノール［ＣＡＳ：６１０－７８－６］（式１７１の化合物）

Figure 0007397075000110

収率 93%, 81 mg （一般的方法Ｉを使用）; 黄色固体; mp 126 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 10.47 (s, 1H), 8.11 (d, J = 2.6 Hz, 1H), 7.54 (dd, J = 9.0, 2.6 Hz, 1H), 7.14 (d, J = 9.0 Hz, 1H); 13C NMR (75 MHz, クロロホルム-d) δ 153.7, 137.6, 125.3, 124.4, 121.5. 4-chloro-3-nitrophenol [CAS:610-78-6] (compound of formula 171)
Figure 0007397075000110
Yield 93%, 81 mg (using general method I); yellow solid; mp 126 °C; 1 H NMR (300 MHz, chloroform-d) δ 10.47 (s, 1H), 8.11 (d, J = 2.6 Hz , 1H), 7.54 (dd, J = 9.0, 2.6 Hz, 1H), 7.14 (d, J = 9.0 Hz, 1H); 13 C NMR (75 MHz, chloroform-d) δ 153.7, 137.6, 125.3, 124.4, 121.5.

シクロプロピル（５－ニトロチオフェン－２－イル）メタノン［ＣＡＳ：１３３００４９－３３－６］（式１７２の化合物）

Figure 0007397075000111

収率 84%, 83 mg (一般的方法Ｉを使用, 19時間); 白色固体; mp 104-105 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 8.52 (d, J = 1.4 Hz, 1H), 8.29 (d, J = 1.5 Hz, 1H), 2.55 (tt, J = 7.7, 4.5 Hz, 1H), 1.35 - 1.24 (m, 2H), 1.21 - 1.08 (m, 2H); 13C NMR (75 MHz, クロロホルム-d) δ 192.2, 145.4, 132.9, 125.1, 17.9, 12.4. Cyclopropyl(5-nitrothiophen-2-yl)methanone [CAS:1330049-33-6] (compound of formula 172)
Figure 0007397075000111
Yield 84%, 83 mg (using general method I, 19 hours); white solid; mp 104-105 °C; 1 H NMR (300 MHz, chloroform-d) δ 8.52 (d, J = 1.4 Hz, 1H ), 8.29 (d, J = 1.5 Hz, 1H), 2.55 (tt, J = 7.7, 4.5 Hz, 1H), 1.35 - 1.24 (m, 2H), 1.21 - 1.08 (m, 2H); 13 C NMR 75 MHz, Chloroform-d) δ 192.2, 145.4, 132.9, 125.1, 17.9, 12.4.

フェニトイン－ＮＯ 2 （式１７３の化合物）

Figure 0007397075000112

異性体の総収率 98%, 145.5 mg （一般的方法Ｉを使用）; 白色固体, mp 235-240 ℃; 左の分子の1H NMR (500 MHz, DMSO-d6) δ 11.3 (s, 1H), 9.51 (s, 1H), 8.29 (d, J= 10.0 Hz, 2H), 7.67 (d, J= 10.0 Hz, 2H); 7.43 - 7.34 (m, 5H); 中央の分子の1H NMR (500 MHz, DMSO-d6) δ 11.3 (s, 1H), 9.5 (s, 1H), 8.30 -8.24 (m, 2H), 7.88 (d, J = 10.0 Hz, 1H), 7.74 (t, 10.0 Hz, 1H), 7.43 - 7.34 (m, 5H), 右の分子の1H NMR (500 MHz, DMSO-d6) δ 11.1 (s, 1H), 9.3 (s, 1H), 8.11 (d, J = 5.0 Hz, 1H), 7.97 (t, J = 5.0 Hz, 1H), 7.98 - 7.91 (m, J = 5.0 Hz, 3H), 7.43 - 7.34 (m, 5H). 混合物の13C NMR (125 MHz, クロロホルム-d) δ 175.3, 174.57, 174.41, 156.44, 156.27, 148.2, 147.6, 147.0, 142.0, 140.4, 135.55, 134.89, 133.8, 130.8, 129.3, 129.2, 128.95, 128.93, 129.91, 128.52, 128.47, 127.0, 126.9, 125.1, 123.2, 123.7, 121.5, 121.4, 70.6, 70.5, 70.1; IR (ATR, ニート): 3048, 1771, 1714, 1519, 1347, 1225, 1095, 852, 691; HRMS (ESI+) C15H11N3O4Naの計算値 (m/z): [M+Na+] 320.0642; 実測値 320.0642. Phenytoin-NO 2 (compound of formula 173)
Figure 0007397075000112
Total yield of isomers 98%, 145.5 mg (using general method I); white solid, mp 235-240 °C; 1 H NMR (500 MHz, DMSO-d 6 ) δ 11.3 (s, 1H), 9.51 (s, 1H), 8.29 (d, J= 10.0 Hz, 2H), 7.67 (d, J= 10.0 Hz, 2H); 7.43 - 7.34 (m, 5H); 1H NMR of the central molecule (500 MHz, DMSO-d 6 ) δ 11.3 (s, 1H), 9.5 (s, 1H), 8.30 -8.24 (m, 2H), 7.88 (d, J = 10.0 Hz, 1H), 7.74 (t, 10.0 Hz, 1H), 7.43 - 7.34 (m, 5H), 1 H NMR of the molecule on the right (500 MHz, DMSO-d 6 ) δ 11.1 (s, 1H), 9.3 (s, 1H), 8.11 (d, J 13C NMR (125 MHz) of the mixture , Chloroform-d) δ 175.3, 174.57, 174.41, 156.44, 156.27, 148.2, 147.6, 147.0, 142.0, 140.4, 135.55, 134.89, 133.8, 130.8, 129.3, 129.2, 128.95, 128.93, 129.91, 128.52, 128.47, 127.0, 126.9, 125.1, 123.2, 123.7, 121.5, 121.4, 70.6, 70.5, 70.1; IR (ATR, NEET): 3048, 1771, 1714, 1519, 1347, 1225, 1095, 852, 691 ; HRMS (ESI+) C 15 H Calculated value of 11 N 3 O 4 Na (m/z): [M+Na + ] 320.0642; Actual value 320.0642.

ニメスリド－ＮＯ 2 （式１７４の化合物）

Figure 0007397075000113
左の分子の収率 76.1%, 134 mg （一般的方法Ｉを使用）; 黄色固体, mp 177.2-178.0 ℃; 1H NMR (400 MHz, クロロホルム-d) δ 10.36 (s, 1H), 8.54 - 8.24 (m, 2H), 8.18 (dd, J = 9.1, 2.6 Hz, 1H), 7.96 (d, J = 2.6 Hz, 1H), 7.82 (d, J = 9.1 Hz, 1H), 7.26 (d, J = 9.2 Hz, 2H), 3.18 (s, 3H); 13C NMR (101 MHz, クロロホルム-d) δ 166.67, 149.31, 148.33, 148.26, 142.28, 131.20, 126.79, 123.33, 121.74, 46.12; IR (ATR, ニート): 3264, 1717, 1586, 1509, 1336, 1226, 1160, 965, 897, 744, 514; HRMS (ESI+) C13H11N3NaO7Sの計算値 (m/z): [M+Na] 376.0212; 実測値 376.0214.
右の分子の収率 23%, 40.5 mg （一般的方法Ｉを使用）; 黄赤色固体, mp 173.1-173.6 ℃; 1H NMR (300 MHz, クロロホルム-d) δ 8.16 (dd, J = 8.2, 1.6 Hz, 1H), 8.06 (dd, J = 9.0, 2.4 Hz, 1H), 7.85 (d, J = 9.0 Hz, 1H), 7.77 (td, J = 8.2, 1.6 Hz, 1H), 7.60 (s, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.56 - 7.46 (m, 1H), 7.33 (dd, J = 8.2, 1.1 Hz, 1H), 3.19 (s, 3H); 13C NMR (75 MHz, クロロホルム-d) δ 147.1, 145.5, 143.6, 141.3, 135.7, 134.3, 127.1, 126.9, 123.4, 120.5, 117.9, 111.1, 40.5; IR (ATR, ニート): 3263, 1599, 1517, 1336, 1267, 1186, 1160, 952, 738, 516; HRMS (ESI+) C13H11N3NaO7Sの計算値 (m/z): [M+Na] 376.0212; 実測値 376.0212. Nimesulide-NO 2 (compound of formula 174)
Figure 0007397075000113
 Yield of molecule on the left 76.1%, 134 mg (using general method I); yellow solid, mp 177.2-178.0 °C; 1 H NMR (400 MHz, chloroform-d) δ 10.36 (s, 1H), 8.54 - 8.24 (m, 2H), 8.18 (dd, J = 9.1, 2.6 Hz, 1H), 7.96 (d, J = 2.6 Hz, 1H), 7.82 (d, J = 9.1 Hz, 1H), 7.26 (d, J = 9.2 Hz, 2H), 3.18 (s, 3H); 13 C NMR (101 MHz, chloroform-d) δ 166.67, 149.31, 148.33, 148.26, 142.28, 131.20, 126.79, 123.33, 121.74, 46 .12; IR (ATR, NEET): 3264, 1717, 1586, 1509, 1336, 1226, 1160, 965, 897, 744, 514; HRMS (ESI+) Calculated value of C 13 H 11 N 3 NaO 7 S (m/z): [M+ Na] 376.0212; Actual value 376.0214.
Yield of molecule on the right 23%, 40.5 mg (using general method I); yellow-red solid, mp 173.1-173.6 °C; 1 H NMR (300 MHz, chloroform-d) δ 8.16 (dd, J = 8.2, 1.6 Hz, 1H), 8.06 (dd, J = 9.0, 2.4 Hz, 1H), 7.85 (d, J = 9.0 Hz, 1H), 7.77 (td, J = 8.2, 1.6 Hz, 1H), 7.60 (s, 1H), 7.57 (d, J = 2.4 Hz, 1H), 7.56 - 7.46 (m, 1H), 7.33 (dd, J = 8.2, 1.1 Hz, 1H), 3.19 (s, 3H); 13 C NMR (75 MHz, Chloroform-d) δ 147.1, 145.5, 143.6, 141.3, 135.7, 134.3, 127.1, 126.9, 123.4, 120.5, 117.9, 111.1, 40.5; IR (ATR, neat): 3263, 159 9, 1517, 1336, 1267, 1186, 1160, 952, 738, 516; HRMS (ESI+) Calculated value of C 13 H 11 N 3 NaO 7 S (m/z): [M+Na] 376.0212; Actual value 376.0212.

セクニダゾール［ＣＡＳ：３３６６－９５－８］（式１７５の化合物）

Figure 0007397075000114

収率 44%, 41 mg (一般的方法Ｉを使用I, 19時間); 白色固体, mp 80.5-81.5 ℃; 1H NMR (300 MHz, アセトニトリル-d3) δ 7.91 (s, 1H), 4.60 - 4.21 (m, 1H), 4.21 - 3.90 (m, 2H), 3.26 (s, 1H), 2.46 (s, 3H), 1.23 (d, J = 5.9 Hz, 3H); 13C NMR (101 MHz, アセトニトリル-d3) δ 151.6, 138.6, 132.3, 66.0, 52.4, 19.7, 13.7; IR (ATR, ニート): 3503, 3136, 1526, 1447, 1388, 1352, 1181, 1083, 932, 839, 741, 490; HRMS (ESI+) C7H12N3O3の計算値 (m/z): [M+H] 186.0873; 実測値 186.0877. Secnidazole [CAS:3366-95-8] (compound of formula 175)
Figure 0007397075000114
Yield 44%, 41 mg (using general method I, 19 hours); white solid, mp 80.5-81.5 °C; 1 H NMR (300 MHz, acetonitrile- d3 ) δ 7.91 (s, 1H), 4.60 13 C NMR (101 MHz, Acetonitrile- d3 ) δ 151.6, 138.6, 132.3, 66.0, 52.4, 19.7, 13.7; IR (ATR, neat): 3503, 3136, 1526, 1447, 1388, 1352, 1181, 1083, 932, 839, 741, 490 ; HRMS (ESI+) Calculated value for C 7 H 12 N 3 O 3 (m/z): [M+H] 186.0873; Actual value 186.0877.

１－（４－ニトロフェニル）－３－（トリフルオロメチル）－１Ｈ－ピラゾール－４－カルボン酸エチル及び１－（２－ニトロフェニル）－３－（トリフルオロメチル）－１Ｈ－ピラゾール－４－カルボン酸エチル（式１７６の化合物）

Figure 0007397075000115

左の分子の収率 83%, 136.5 mg （一般的方法ＩＩを使用）; 黄色固体; mp 115.3-116.5 ℃; 1H NMR (400 MHz, クロロホルム-d) δ 8.41 (d, J = 9.0 Hz, 2H), 7.75 - 7.59 (m, 2H), 4.41 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, クロロホルム-d) δ 160.5, 148.2, 143.9, 143.3, 132.74(q, J = 40.5 Hz), 126.8, 124.6, 118.95 (q, J = 271.7 Hz), 117.9 (q, J = 1.1 Hz), 61.6, 14.1; 19F NMR (376 MHz, クロロホルム-d) δ -54.94; IR (ATR, ニート): 1735, 1523, 1345, 1224, 1151, 1018, 970, 855, 756, 704; HRMS (ESI+) C13H11F3N3O4の計算値 (m/z): [M+H] 330.0696; 実測値 330.0697.
右の分子の収率 10%, 16.5 mg （一般的方法ＩＩを使用）; 黄色固体; mp 119-120 ℃; 1H NMR (400 MHz, クロロホルム-d) δ 8.23 (dd, J = 8.0, 1.7 Hz, 1H), 8.20 - 8.15 (m, 1H), 7.88 - 7.71 (m, 2H), 7.56 (dd, J = 7.7, 1.6 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H); 13C NMR (101 MHz, クロロホルム-d) δ 160.5 (q, J = 1.0 Hz), 144.9, 143.5, 134.3 (q, J = 40.3 Hz), 133.9, 132.9, 131.4, 129.7 (q, J = 1.0 Hz), 125.7, 118.9 (q, J = 271.6 Hz), 116.9 (q, J = 1.5 Hz), 61.4, 14.1; 19F NMR (376 MHz, クロロホルム-d) δ -56.66; IR (ATR, ニート): 2914, 1724, 1565, 1385, 1249, 1145, 1067, 972, 752; HRMS (ESI+) C13H10F3N3O4Naの計算値 (m/z): [M+Na] 352.0516; 実測値 352.0515. Ethyl 1-(4-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazole-4-carboxylate and 1-(2-nitrophenyl)-3-(trifluoromethyl)-1H-pyrazole-4- Ethyl carboxylate (compound of formula 176)
Figure 0007397075000115
Yield of molecule on the left 83%, 136.5 mg (using general method II); yellow solid; mp 115.3-116.5 °C; 1 H NMR (400 MHz, chloroform-d) δ 8.41 (d, J = 9.0 Hz, 2H), 7.75 - 7.59 (m, 2H), 4.41 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, chloroform-d) δ 160.5, 148.2, 143.9, 143.3, 132.74(q, J = 40.5 Hz), 126.8, 124.6, 118.95 (q, J = 271.7 Hz), 117.9 (q, J = 1.1 Hz), 61.6, 14.1 ; , Chloroform-d) δ -54.94; IR (ATR, neat): 1735, 1523, 1345, 1224, 1151, 1018, 970, 855, 756, 704; HRMS (ESI+) C 13 H 11 F 3 N 3 O 4 Calculated value (m/z): [M+H] 330.0696; measured value 330.0697.
Yield of molecule on the right 10%, 16.5 mg (using General Method II); yellow solid; mp 119-120 °C; 1 H NMR (400 MHz, chloroform-d) δ 8.23 (dd, J = 8.0, 1.7 Hz, 1H), 8.20 - 8.15 (m, 1H), 7.88 - 7.71 (m, 2H), 7.56 (dd, J = 7.7, 1.6 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H); 13 C NMR (101 MHz, chloroform-d) δ 160.5 (q, J = 1.0 Hz), 144.9, 143.5, 134.3 (q, J = 40.3 Hz), 133.9, 132.9 19 F NMR (376 MHz, chloroform-d) δ -56.66; IR (ATR, NEET): 2914, 1724, 1565, 1385, 1249, 1145, 1067, 972, 752; HRMS (ESI+) Calculated value of C 13 H 10 F 3 N 3 O 4 Na (m/ z): [M+Na] 352.0516; Actual value 352.0515.

プロシミドン-ＮＯ 2 （式１７７の化合物）

Figure 0007397075000116

収率 91%, 150 mg (一般的方法Ｉを使用, 19時間); 黄色固体; mp 199.3-200.0 ℃; 1H NMR (400 MHz, クロロホルム-d) δ 7.58 (d, J = 2.1 Hz, 1H), 7.33 (s, 1H), 1.91 (d, J = 4.8 Hz, 1H), 1.48 (s, 6H), 1.22 (d, J = 4.8 Hz, 1H); 13C NMR (101 MHz, クロロホルム-d) δ 174.7, 144.5, 137.5, 131.1, 129.0, 128.4, 127.1, 32.6, 30.7, 9.9; IR (ATR, ニート): 3074, 1780, 1720, 1571, 1442, 1360, 1143, 1143, 1110, 806, 731, 522; HRMS (ESI+) C13H10F3N3O4Naの計算値 (m/z): [M+H] 329.009; 実測値 329.0089. Procymidone-NO 2 (compound of formula 177)
Figure 0007397075000116
Yield 91%, 150 mg (using general method I, 19 hours); yellow solid; mp 199.3-200.0 °C; 1 H NMR (400 MHz, chloroform-d) δ 7.58 (d, J = 2.1 Hz, 1H ), 7.33 (s, 1H), 1.91 (d, J = 4.8 Hz, 1H), 1.48 (s, 6H), 1.22 (d, J = 4.8 Hz, 1H); 13 C NMR (101 MHz, chloroform-d ) δ 174.7, 144.5, 137.5, 131.1, 129.0, 128.4, 127.1, 32.6, 30.7, 9.9; IR (ATR, NEET): 3074, 1780, 1720, 1571, 1442, 1360, 1143, 1143, 1110, 806, 731 , 522; HRMS (ESI+) Calculated value of C 13 H 10 F 3 N 3 O 4 Na (m/z): [M+H] 329.009; Actual value 329.0089.

アルブチンペラセテート－ＮＯ 2 （式１７８の化合物）

Figure 0007397075000117

収率 74%, 195 mg （一般的方法ＩＩを使用）; 黄色固体, mp 149.6-150.0 ℃; 1H NMR (300 MHz, アセトニトリル-d3) δ 7.63 (d, J = 2.7 Hz, 1H), 7.52 - 7.34 (m, 2H), 5.42 - 5.31 (m, 2H), 5.30 - 5.11 (m, 2H), 4.24 (qd, J = 12.4, 3.9 Hz, 2H), 4.15 - 4.02 (m, 1H), 2.29 (d, J = 3.3 Hz, 3H), 2.09 - 1.93 (m, 15H); 13C NMR (75 MHz, アセトニトリル-d3) δ 169.9, 169.5, 169.2, 168.9, 168.9, 146.4, 145.2, 140.4, 127.3, 119.2, 118.2, 99.2, 71.8, 71.6, 69.9, 67.6, 61.2, 19.8, 19.6, 19.6, 19.5, 19.5; IR (ATR, ニート): 1751, 1533, 1366, 1227, 1185, 1038, 926, 597; HRMS (ESI+) C22H25KNO14の計算値 (m/z): [M+K] 566.0907; 実測値 566.0898. Arbutin peracetate-NO 2 (compound of formula 178)
Figure 0007397075000117
Yield 74%, 195 mg (using general method II); yellow solid, mp 149.6-150.0 °C; 1 H NMR (300 MHz, acetonitrile- d3 ) δ 7.63 (d, J = 2.7 Hz, 1H), 7.52 - 7.34 (m, 2H), 5.42 - 5.31 (m, 2H), 5.30 - 5.11 (m, 2H), 4.24 (qd, J = 12.4, 3.9 Hz, 2H), 4.15 - 4.02 (m, 1H), 2.29 (d, J = 3.3 Hz, 3H), 2.09 - 1.93 (m, 15H); 13 C NMR (75 MHz, acetonitrile-d 3 ) δ 169.9, 169.5, 169.2, 168.9, 168.9, 146.4, 145.2, 140.4 , IR (ATR, NEET): 1751, 1533, 1366, 1227, 1185, 1038, 926, 597 ; Calculated value of HRMS (ESI+) C 22 H 25 KNO 14 (m/z): [M+K] 566.0907; Actual value 566.0898.

ノルヒドロカプサイシン－ＮＯ 2 （式１７９の化合物）

Figure 0007397075000118

収率 94%, 159 mg （一般的方法Ｉを使用）; 黄色固体; mp 121.5-122.5 ℃; 1H NMR (400 MHz, クロロホルム-d) δ 10.72 (s, 1H), 7.57 (d, J = 1.9 Hz, 1H), 7.12 (d, J = 1.9 Hz, 1H), 5.99 (s, 1H), 4.41 (d, J = 6.0 Hz, 2H), 3.94 (s, 3H), 2.26 (t, J = 7.6 Hz, 2H), 1.67 (p, J = 7.4 Hz, 2H), 1.39 - 1.21 (m, 11H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (101 MHz, クロロホルム-d) δ 173.3, 150.2, 145.7, 133.4, 130.2, 117.5, 114.2, 56.7, 42.7, 36.7, 31.8, 29.3, 29.1, 25.7, 22.6, 14.1; IR (ATR, ニート): 3296, 2920, 2847, 1642, 1532, 1327, 1268, 1220, 1130, 1060, 857, 689; HRMS (ESI+) C17H30N3O5の計算値 (m/z): [M+NH4] 356.2180; 実測値 356.2186. Norhydrocapsaicin-NO 2 (compound of formula 179)
Figure 0007397075000118
Yield 94%, 159 mg (using general method I); yellow solid; mp 121.5-122.5 °C; 1 H NMR (400 MHz, chloroform-d) δ 10.72 (s, 1H), 7.57 (d, J = 1.9 Hz, 1H), 7.12 (d, J = 1.9 Hz, 1H), 5.99 (s, 1H), 4.41 (d, J = 6.0 Hz, 2H), 3.94 (s, 3H), 2.26 (t, J = 13 C NMR (101 MHz, chloroform-d) δ 173.3, 150.2, 145.7, 133.4, 130.2, 117.5, 114.2, 56.7, 42.7, 36.7, 31.8, 29.3, 29.1, 25.7, 22.6, 14.1; IR (ATR, NEET): 3296, 2920, 2847, 1642, 1532, 1327, 1268, 1220, 1130, 1060, 857, 689; HRMS (ESI+) Calculated value of C 17 H 30 N 3 O 5 (m/z): [M+NH 4 ] 356.2180; Actual value 356.2186.

Ｎ－Ｂｏｃ－ｐ－ニトロ－Ｌ－フェニルアラニン［ＣＡＳ：３３３０５－７７－０］及びＮ－Ｂｏｃ－ｏ－ニトロ－Ｌ－フェニルアラニン［ＣＡＳ：１８５１４６－８４－３］（式１８０の化合物）

Figure 0007397075000119

左の分子の収率 51%, 125 mg （一般的方法Ｉを使用）, 黄色固体; mp 111.9-112.6 ℃; 1H NMR (300 MHz, DMSO-d6) δ 12.71 (s, 1H), 8.15 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.6 Hz, 1H), 4.19 (ddd, J = 10.5, 8.5, 4.5 Hz, 1H), 3.18 (dd, J = 13.7, 4.6 Hz, 1H), 2.96 (dd, J = 13.7, 10.5 Hz, 1H), 1.30 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ 173.0, 155.3, 146.4, 146.2, 130.4, 123.1, 78.1, 54.5, 36.2, 28.0.
右の分子の収率 13%, 20 mg （一般的方法Ｉを使用）, 黄色固体, mp 129-131 ℃; 1H NMR (300 MHz, DMSO-d6) δ 12.36 (s, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.72 (dt, J = 13.8, 6.9 Hz, 3H), 7.50 (t, J = 7.5 Hz, 1H), 5.33 (q, J = 8.3 Hz, 1H), 2.91 - 2.54 (m, 2H), 1.31 (s, 9H); 13C NMR (75 MHz, DMSO-d6) δ 171.2, 154.7, 147.9, 138.3, 128.2, 128.2, 123.9, 78.2, 46.9, 28.1. N-Boc-p-nitro-L-phenylalanine [CAS: 33305-77-0] and N-Boc-o-nitro-L-phenylalanine [CAS: 185146-84-3] (compounds of formula 180)
Figure 0007397075000119
Yield of molecule on the left 51%, 125 mg (using general method I), yellow solid; mp 111.9-112.6 °C; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.71 (s, 1H), 8.15 (d, J = 8.6 Hz, 2H), 7.53 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.6 Hz, 1H), 4.19 (ddd, J = 10.5, 8.5, 4.5 Hz, 1H) , 3.18 (dd, J = 13.7, 4.6 Hz, 1H), 2.96 (dd, J = 13.7, 10.5 Hz, 1H), 1.30 (s, 9H); 13 C NMR (75 MHz, DMSO-d 6 ) δ 173.0 , 155.3, 146.4, 146.2, 130.4, 123.1, 78.1, 54.5, 36.2, 28.0.
Yield of molecule on the right 13%, 20 mg (using General Method I), yellow solid, mp 129-131 °C; 1 H NMR (300 MHz, DMSO-d 6 ) δ 12.36 (s, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.72 (dt, J = 13.8, 6.9 Hz, 3H), 7.50 (t, J = 7.5 Hz, 1H), 5.33 (q, J = 8.3 Hz, 1H), 2.91 - 2.54 (m, 2H), 1.31 (s, 9H); 13 C NMR (75 MHz, DMSO-d 6 ) δ 171.2, 154.7, 147.9, 138.3, 128.2, 128.2, 123.9, 78.2, 46.9, 28.1.

Claims (15)

少なくとも１つの置換又は非置換芳香環又はヘテロ芳香環を含む化合物（Ａ）と、
式（Ｉ）
Figure 0007397075000120
 の化合物を反応させる工程を含む、ニトロ化合物を調製するための方法であって、
前記ヘテロ芳香環は、酸素、硫黄、リン、セレン、及び窒素から成る群から選択される少なくとも１つのヘテロ原子を含み、
式中、Ｙは水素及びニトロから成る群から選択される、方法。 A compound (A) containing at least one substituted or unsubstituted aromatic ring or heteroaromatic ring;
Formula (I)
Figure 0007397075000120
 A method for preparing a nitro compound, the method comprising the step of reacting a compound of
The heteroaromatic ring contains at least one heteroatom selected from the group consisting of oxygen, sulfur, phosphorus, selenium, and nitrogen,
wherein Y is selected from the group consisting of hydrogen and nitro. 前記化合物（Ａ）の芳香環又はヘテロ芳香環が、ジフルオロメトキシ、トリフルオロメトキシ、ジフルオロメチルチオ、トリフルオロメチルチオ、クロロ、ヨード、メトキシ、エトキシ、プロポキシ、ブトキシ、アミノ、メチルアミノ、ジメチルアミノ、ホルミル、メトキシカルボニル、エトキシカルボニル、ｔｅｒｔ－ブトキシカルボニル、塩化アシル、酸無水物、カルボン酸エステル、スルホン酸エステル、カルボキシ、ケタール、アセタール、ヒドラゾン、及び４，４，５，５－テトラメチル－１，３，２－ジオキサボロラニルから成る群から選択される少なくとも１つの基を含む、請求項１に記載の方法。 The aromatic ring or heteroaromatic ring of the compound (A) is difluoromethoxy, trifluoromethoxy, difluoromethylthio, trifluoromethylthio, chloro, iodo, methoxy, ethoxy, propoxy, butoxy, amino, methylamino, dimethylamino, formyl, Methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, acyl chloride, acid anhydride, carboxylic acid ester, sulfonic acid ester , carboxy, ketal, acetal, hydrazone, and 4,4,5,5-tetramethyl-1,3, 2. The method of claim 1, comprising at least one group selected from the group consisting of 2-dioxaborolanyl. 化合物（Ａ）の前記芳香環又はヘテロ芳香環が少なくとも１つの電子供与基を残基として含み、前記電子供与基は、好ましくは、アミノ、カルバモイル、アルキルアミノカルボニル、カルボキサミド、メルカプト、アルキルチオ、ヒドロキシ、アルコキシ、アルキル、アシルオキシ、アリール、ヘテロアリール、アルケニル、及びアルキニルから成る群から選択される、請求項１又は２に記載の方法。 The aromatic ring or heteroaromatic ring of compound (A) contains at least one electron donating group as a residue, and the electron donating group is preferably amino, carbamoyl, alkylaminocarbonyl, carboxamide, mercapto, alkylthio, hydroxy. , alkoxy, alkyl, acyloxy, aryl, heteroaryl, alkenyl, and alkynyl. 化合物（Ａ）の前記芳香環又はヘテロ芳香環が少なくとも１つの電子求引基を残基として含み、前記電子求引基は、好ましくは、フルオロ、クロロ、ブロモ、ヨード、アシル、カルボキシ、ベンゾイル、カルボニル、アルデヒド、アリールスルホニル、ハロアルキル、シアノ、及び２，５－ジオキソピロリジニルから成る群から選択される、請求項１～３のいずれか１項に記載の方法。 The aromatic ring or heteroaromatic ring of compound (A) contains at least one electron-withdrawing group as a residue, and the electron-withdrawing group is preferably fluoro, chloro, bromo, iodo, acyl, carboxy, benzoyl. , carbonyl, aldehyde, arylsulfonyl, haloalkyl, cyano, and 2,5 -dioxopyrrolidinyl. 前記化合物（Ａ）が、５員又は６員の置換又は非置換の芳香環又はヘテロ芳香環を含むか、又はそれからなる、請求項１～４のいずれか１項に記載の方法。 The method according to any one of claims 1 to 4 , wherein the compound (A) comprises or consists of a 5- or 6-membered substituted or unsubstituted aromatic or heteroaromatic ring. 前記化合物（Ａ）が、置換されていてもされていなくてもよい２～５個の芳香環又はヘテロ芳香環を含む縮合芳香環又はヘテロ芳香環系を含むか、又はそれからなる、請求項１～４のいずれか１項に記載の方法。 1. The compound (A) comprises or consists of a fused aromatic ring or heteroaromatic ring system containing 2 to 5 aromatic or heteroaromatic rings, which may be substituted or unsubstituted. 4. The method according to any one of items 4 to 4. 前記ヘテロ芳香環又は環系が、ピロール、チオフェン、フラン、イミダゾール、チアゾール、ピリミジン、ピリジン、ピラジン、ピリダジン、イソキサゾール、オキサゾール、インドール、イソインドール、インドリジン、キノリン、イソキノリン、プリン、カルバゾール、ジベンゾフラン、アクリジン、プリン、グアニン、キサンチン、尿酸、ベンゾチオフェン、ベンゾフラン、ジベンゾチオフェン、チアンスレン、キサンテン、フェノキサチイン、イソキノリン、フタラジン、１，８－ナフチドリン、キナゾリン、キノキサリン、シンノリン、プテリジン、ペリミジン、１，７－フェナントロリン、フェナジン、ホスフィンドール、フタルイミド、フラザン、及びホスフィノリン、最も好ましくは、ピリジン、ピリミジン、フラン、及びフタルイミドから成る群から選択される、請求項１～６のいずれか１項に記載の方法。 The heteroaromatic ring or ring system is pyrrole, thiophene, furan, imidazole, thiazole, pyrimidine, pyridine, pyrazine, pyridazine, isoxazole, oxazole, indole, isoindole, indolizine, quinoline, isoquinoline, purine, carbazole, dibenzofuran, acridine , purine, guanine, xanthine, uric acid, benzothiophene, benzofuran, dibenzothiophene, thianthrene, xanthene, phenoxathiin, isoquinoline, phthalazine, 1,8-naphthydrine, quinazoline, quinoxaline, cinnoline, pteridine, perimidine, 1,7-phenanthroline , phenazine, phosphhindole, phthalimide, furazane, and phosphinoline, most preferably pyridine, pyrimidine, furan, and phthalimide . 前記芳香環又は環系が、ベンゼン、ペンタレン、インデン、インダン、ナフタレン、１，１'－ビナフタレン、アズレン、ヘプタレン、ビフェニレン、ａｓ－インダセン、ｓ－インダセン、アセナフチレン、フルオレンフェナレン、フェナントレン、アントラセン、フルオランテン、アセフェナントリレン、アセアントリレントリフェニレン、ピレンクリセン、ナフタセン、プレイアデン、ピセン、及びペリレン、最も好ましくはベンゼンから成る群から選択される、請求項１～６のいずれか１項に記載の方法。 The aromatic ring or ring system is benzene, pentalene, indene, indane, naphthalene, 1,1'-binaphthalene, azulene, heptalene, biphenylene, as-indacene, s-indacene, acenaphthylene, fluorenephenalene, phenanthrene, anthracene, fluoranthene. , acephenanthrylene, aceantrylene triphenylene, pyrene chrysene, naphthacene, pleiadene, picene, and perylene , most preferably benzene. 前記式（Ｉ）の化合物が式（Ｉａ）
Figure 0007397075000121
 の化合物である、請求項１～８のいずれか１項に記載の方法。 The compound of formula (I) is of formula (Ia)
Figure 0007397075000121
 The method according to any one of claims 1 to 8 , which is a compound of. 前記式（Ｉ）の化合物が式（Ｉｂ）
Figure 0007397075000122
 の化合物である、請求項１～８のいずれか１項に記載の方法。 The compound of formula (I) is of formula (Ib)
Figure 0007397075000122
 The method according to any one of claims 1 to 8, which is a compound of. 前記反応が、ヘキサフルオロイソプロパノール、アセトニトリル、ニトロメタン、塩化メチレン、トリフルオロエタノール、テトラヒドロフラン、ヘキサン、ベンゼン、及びトルエン、又はこれらの混合物、好ましくはヘキサフルオロイソプロパノール及びアセトニトリルから成る群から選択される溶媒中で実施される、請求項１～１０のいずれか１項に記載の方法。 The reaction is carried out in a solvent selected from the group consisting of hexafluoroisopropanol, acetonitrile, nitromethane, methylene chloride, trifluoroethanol, tetrahydrofuran, hexane, benzene, and toluene, or mixtures thereof, preferably hexafluoroisopropanol and acetonitrile. A method according to any one of claims 1 to 10 , which is carried out. 前記反応が、触媒、好ましくはプロトン供与酸又はルイス酸の存在下で実施される、請求項１～１１のいずれか１項に記載の方法。 Process according to any one of claims 1 to 11 , wherein the reaction is carried out in the presence of a catalyst, preferably a proton-donating acid or a Lewis acid. 前記プロトン供与酸が、酢酸、トリメチル酢酸、トリクロロ酢酸、トリフルオロ酢酸、安息香酸、及びこれらの混合物、好ましくは酢酸及びトリメチル酢酸から成る群から選択される、請求項１２に記載の方法。 13. The method according to claim 12, wherein the proton-donating acid is selected from the group consisting of acetic acid, trimethylacetic acid, trichloroacetic acid, trifluoroacetic acid, benzoic acid, and mixtures thereof, preferably acetic acid and trimethylacetic acid. 前記ルイス酸が、鉄（ＩＩ）トリフラート、鉄（ＩＩＩ）トリフラート、マグネシウム（ＩＩ）トリフラート、亜鉛（ＩＩ）トリフラート、銅（ＩＩ）トリフラート、臭化鉄（ＩＩ）、臭化鉄（ＩＩＩ）、及び過塩素酸マグネシウム、好ましくは過塩素酸マグネシウムから成る群から選択される、請求項１２に記載の方法。 The Lewis acid is iron (II) triflate, iron (III) triflate, magnesium (II) triflate, zinc (II) triflate, copper (II) triflate, iron (II) bromide, iron (III) bromide, and 13. The method according to claim 12 , wherein the method is selected from the group consisting of magnesium perchlorate, preferably magnesium perchlorate. 芳香環又はヘテロ芳香環を含む化合物（Ａ）のニトロ化剤としての式（Ｉ）
Figure 0007397075000123
 （式中、Ｙは水素及びニトロから成る群から選択される）の化合物の使用。 Formula (I) as a nitration agent for a compound (A) containing an aromatic ring or a heteroaromatic ring
Figure 0007397075000123
 wherein Y is selected from the group consisting of hydrogen and nitro.
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